documents.irevues.inist.frdocuments.irevues.inist.fr/bitstream/handle/2042/... · in Oncology and Haematology The PDF version of the Atlas of Genetics and Cytogenetics in Oncology

Volume 1 - Number 1 May - September 1997

Volume 19 - Number 5 May 2015

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with

the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific

Research (CNRS) on its electronic publishing platform I-Revues.

Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.

Atlas of Genetics and Cytogenetics

in Oncology and Haematology

INIST-CNRS OPEN ACCESS JOURNAL

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematologyis a peer reviewed on-line journal in open access,

devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.

It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology.

One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the

clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer

genetics.The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university

(university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using

information technology, between the increasing amount of knowledge and the individual, having to use the information.

Towards a personalized medicine of cancer.

It presents structured review articles ("cards") on:

1- Genes,

2- Leukemias,

3- Solid tumors,

4- Cancer-prone diseases, and also

5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics.

It also present

6- Case reports in hematology and

7- Educational items in the various related topics for students in Medicine and in Sciences.

The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.

See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf

Editorial correspondance

Jean-LoupHuret, MD, PhD,

Genetics, Department of Medical Information,

University Hospital

F-86021 Poitiers, France

phone +33 5 49 44 45 46

[email protected]@AtlasGeneticsOncology.org

.

Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non

profitorganisation, and by the INstitute for Scientific and Technical Information of

the French National Center for Scientific Research (INIST-CNRS) since 2008.

The Atlas is hosted by INIST-CNRS (http://www.inist.fr)

Staff: Vanessa Le Berre

Philippe Dessen is the Database Director of the on-line version (Gustave Roussy Institute – Villejuif – France).

Publisher Contact:INIST-CNRS

Mailing Address:Catherine Morel, 2,Allée du Parc de Brabois, CS 10130, 54519 Vandoeuvre-lès-Nancy France.

Email Address:[email protected]

Articles of the ATLAS are free in PDF format, and metadata are available on the web in Dublin Core XML format and freely

harvestable.A Digital object identifier (DOI®), recorded at the International Agency CrossRefhttp://www.crossref.org/ is

assigned to each article.

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

http://international.inist.fr/

http://www.cnrs.fr/index.html

http://irevues.inist.fr/



mailto:[email protected]


http://www.crossref.org/

http://www.atlasgeneticsoncology.org/

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with

the Institute for Scientific and Technical Information (INstitut de l’InformationScientifique et Technique - INIST) of the French National Center for Scientific

Research (CNRS) on its electronic publishing platform I-Revues.

Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.




Editor-in-Chief Jean-Loup Huret (Poitiers, France)

Board Members

SreeparnaBanerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected]

Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected]

Judith Bovée 2300 RC Leiden, The Netherlands; [email protected]

Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy;

[email protected]

Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected]

François Desangles IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 91223 Bretigny-sur-Orge, France; [email protected]

Enric Domingo Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford,

OX37BN, UK [email protected]

AyseElifErson-

Bensan Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected]

Ad Geurts van

Kessel

Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life

Sciences, 6500 HB Nijmegen, The Netherlands; [email protected]

Oskar A. Haas Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna,

Children's Cancer Research Institute Vienna, Vienna, Austria. [email protected]

Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected]

NylaHeerema Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; [email protected]

SakariKnuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland;

[email protected]

Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy;

l.larizza@auxologico

RoderickMcLeod Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell

Cultures, Braunschweig, Germany; [email protected]

Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy;

[email protected]

Fredrik Mertens Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; [email protected]

Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected]

Felix Mitelman Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden;

[email protected]

HossainMossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected]

Stefan Nagel Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell

Cultures, Braunschweig, Germany; [email protected]

Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France;

[email protected]

Susana Raimondi Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250,

Memphis, Tennessee 38105-3678, USA; [email protected]

Clelia Tiziana Storlazzi

Department of Biology, University of Bari, Bari, Italy; [email protected]

Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected]

Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France;

[email protected]

Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected]

Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA)

- Italy; [email protected]

Franck Viguié Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital

Universitaire Necker-Enfants Malades, 75015 Paris, France; [email protected]



http://irevues.inist.fr/






Volume 19, Number 5, May 2015

Table of contents

Gene Section

RREB1 (Ras Responsive Element Binding Protein 1) 316 Renty B Franklin, Leslie C Costello

ZMYND10 (zinc finger, MYND-type containing 10) 319 Xiangning Zhang, Michael I Lerman, Zhiwei He

ILK (integrin-linked kinase) 324 Isabel Serrano, Paul McDonald, Shoukat Dedhar

KITLG (KIT ligand) 333 Alessandro Beghini, Francesca Lazzaroni

ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase) 337 Samuel J Klempner, Sai-Hong Ou

MICA (MHC class I polypeptide-related sequence A) 340 Zain Ahmed, Medhat Askar

Leukaemia Section

t(11;21)(p14;q22) RUNX1/KIAA1549L 349 Akihiro Abe

t(4;17)(q12;q21) FIP1L1/RARA 352 Adriana Zamecnikova

Deep Insight Section

The nuclear pore complex: structure and function 355 Vincent Duheron, Birthe Fahrenkrog

Gene Section Short Communication

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5) 316




RREB1 (Ras Responsive Element Binding Protein 1) Renty B Franklin, Leslie C Costello

Department of Oncology and Diagnostic Sciences, Dental School and The Greenebaum Cancer

Center, University of Maryland, Baltimore, MD, 21201, USA (RBF, LCC)

Published in Atlas Database: February 2014

Online updated version : http://AtlasGeneticsOncology.org/Genes/RREB1ID51424ch6p24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62117/02-2014-RREB1ID51424ch6p24.pdf DOI: 10.4267/2042/62117

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Review on RREB1, with data on DNA/RNA, on the

protein encoded and where the gene is implicated.

Identity Other names: FINB, HNT, LZ321, RREB-1, Zep-

1

HGNC (Hugo): RREB1

Location: 6p24.3

DNA/RNA

Description

The RREB1 gene is 144384 bp. The mRNA is 8568

bp and codes a protein of 1742 amino acids. Nine

splice variants of RREB1 are predicted. Variant 1

contains 13 coding exons.

Transcription

Five isoforms of RREB1 designated RREB1 alpha,

RREB1 beta, RREB1 delta, RREB1 gamma and

RREB1 epsilon are expressed through alternative

splicing.

Pseudogene

None reported.

Protein

Description

RREB1 is a zinc finger nuclear protein of 1742

amino acids that contains 15 zinc fingers of the

C2H2 type and belongs to the Krueppel zinc-finger

protein family. RREB1 protein-protein interactions

include NEUROD1 (Ray et al., 2003) and AR

(Mukhopadhyay et al., 2007).

Expression

RREB1 is ubiquitously expressed in most tissues;

however, it may not be expressed in brain.

Localisation

RREB1 expression is localized to nucleus speckle

(Date et al., 2004; Fujimoto-Nishiyama et al.,

1997).

Schematic diagram of Homo sapiens RREB1 protein showing clusters of conserved zinc figures (ZnF).

RREB1 (Ras Responsive Element Binding Protein 1) Franklin RB, Costello LC


RREB1 expression in normal and prostate cancer tissue sections.

Function

RREB1 binds specifically to the ras-responsive

element (RRE) of genes to activate promoter

activity and gene transcription. It is involved in

regulation of calcitonin expression (Thiagalingam

et al., 1996). RREB1 is reported to both activate

and repress transcription (Chen et al., 2010).

RREB1 reportedly negatively regulates the

transcriptional activity of the androgen receptor

(Mukhopadhyay et al., 2007). RREB1 is reported to

play a role in cell to cell adhesion and regulation of

cell movement (Melani et al., 2008). The specific

roles of the individual spliced forms are not well

defined. RREB1 alpha is not required for

proliferation of bladder cancer lines; however,

RREB1 beta may be required (Nitz et al., 2011).

Homology

With members of the Krueppel family of zinc

finger proteins.

Mutations

Note

No disease related mutations are reported.

Implicated in

Colorectal cancer

Note

RREB1 is implicated in Ras signaling pathways.

RREB1 is activated through phosphorylation by the

MAPK pathway in colorectal cancer (Kent et al.,

2013). RREB may play an important role in the

development of the primitive gut tube (Lee et al.,

2012).

Prostate adenocarcinoma.

Note

RREB1 represses the expression of ZIP1 zinc

transporter in prostate epithelial cells. Up-

regulation of RREB1 in prostate cancer may lead to

loss of ZIP1 expression, zinc accumulation and

progression of prostate cancer (Milon et al., 2010;

Zou et al., 2011).

Pancreatic cancer

Note

The zinc levels are markedly decreased in

pancreatic cancer.

The loss of zinc removes its cytotoxic effects on

malignant cells. The change in zinc level is

associated with decreased expression of the ZIP3

zinc transporter.

Recent studies demonstrate that ZIP3 and RREB1

are markedly down regulated with cellular zinc

levels.

In addition, these changes in zinc, ZIP3 and RREB1

are apparent in PanIn lesions, which are thought to

be precancerous lesions leading to ductal

adenocarcinoma.

Results suggest that down regulation of RREB1

causes down regulation of ZIP3, which results in

loss of zinc accumulation in premalignant

pancreatic ductal cells (Costello et al., 2012).

References Thiagalingam A, De Bustros A, Borges M, Jasti R, Compton D, Diamond L, Mabry M, Ball DW, Baylin SB, Nelkin BD. RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas. Mol Cell Biol. 1996 Oct;16(10):5335-45

Fujimoto-Nishiyama A, Ishii S, Matsuda S, Inoue J, Yamamoto T. A novel zinc finger protein, Finb, is a transcriptional activator and localized in nuclear bodies. Gene. 1997 Aug 22;195(2):267-75

Ray SK, Nishitani J, Petry MW, Fessing MY, Leiter AB. Novel transcriptional potentiation of BETA2/NeuroD on the

RREB1 (Ras Responsive Element Binding Protein 1) Franklin RB, Costello LC


secretin gene promoter by the DNA-binding protein Finb/RREB-1. Mol Cell Biol. 2003 Jan;23(1):259-71

Date S, Nibu Y, Yanai K, Hirata J, Yagami K, Fukamizu A. Finb, a multiple zinc finger protein, represses transcription of the human angiotensinogen gene. Int J Mol Med. 2004 May;13(5):637-42

Mukhopadhyay NK, Cinar B, Mukhopadhyay L, Lutchman M, Ferdinand AS, Kim J, Chung LW, Adam RM, Ray SK, Leiter AB, Richie JP, Liu BC, Freeman MR. The zinc finger protein ras-responsive element binding protein-1 is a coregulator of the androgen receptor: implications for the role of the Ras pathway in enhancing androgenic signaling in prostate cancer. Mol Endocrinol. 2007 Sep;21(9):2056-70

Oxford G, Smith SC, Hampton G, Theodorescu D. Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector. Oncogene. 2007 Nov 1;26(50):7143-52

Melani M, Simpson KJ, Brugge JS, Montell D. Regulation of cell adhesion and collective cell migration by hindsight and its human homolog RREB1. Curr Biol. 2008 Apr 8;18(7):532-7

Chen RL, Chou YC, Lan YJ, Huang TS, Shen CK. Developmental silencing of human zeta-globin gene expression is mediated by the transcriptional repressor RREB1. J Biol Chem. 2010 Apr 2;285(14):10189-97

Kent OA, Chivukula RR, Mullendore M, Wentzel EA, Feldmann G, Lee KH, Liu S, Leach SD, Maitra A, Mendell

JT. Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway.

Genes Dev. 2010 Dec 15;24(24):2754-9

Milon BC, Agyapong A, Bautista R, Costello LC, Franklin RB. Ras responsive element binding protein-1 (RREB-1) down-regulates hZIP1 expression in prostate cancer cells. Prostate. 2010 Feb 15;70(3):288-96

Nitz MD, Harding MA, Smith SC, Thomas S, Theodorescu D. RREB1 transcription factor splice variants in urologic cancer. Am J Pathol. 2011 Jul;179(1):477-86

Zou J, Milon BC, Desouki MM, Costello LC, Franklin RB. hZIP1 zinc transporter down-regulation in prostate cancer involves the overexpression of ras responsive element binding protein-1 (RREB-1). Prostate. 2011 Feb 25;

Costello LC, Zou J, Desouki MM, Franklin RB. Evidence for changes in RREB-1, ZIP3, and Zinc in the early development of pancreatic adenocarcinoma. J Gastrointest Cancer. 2012 Dec;43(4):570-8

Lee DH, Ko JJ, Ji YG, Chung HM, Hwang T. Proteomic identification of RREB1, PDE6B, and CD209 up-regulated in primitive gut tube differentiated from human embryonic stem cells. Pancreas. 2012 Jan;41(1):65-73

This article should be referenced as such:

Franklin RB, Costello LC. RREB1 (Ras Responsive Element Binding Protein 1). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5):316-318.

Gene Section Review





ZMYND10 (zinc finger, MYND-type containing 10) Xiangning Zhang, Michael I Lerman, Zhiwei He

Guangdong Medical College, Dongguan, Guangdong 523808, China (XZ, ZH), Affina

Biotechnologies, Inc., Stamford, CT USA (MIL)

Published in Atlas Database: July 2014

Online updated version : http://AtlasGeneticsOncology.org/Genes/ZMYND10ID45815ch3p21.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62118/07-2014-ZMYND10ID45815ch3p21.pdf DOI: 10.4267/2042/62118


Abstract The candidate tumor suppressor gene

ZMYND10/BLU, is located on the minimal deleted

fragment of 110 kb in chromosomal region 3p21.3.

It was initially identified by PCR in search of the b-

catenin homolog in lung cancer. BLU codes for a

protein with 440 amino acid residues, which

contains a zinc finger myelogenous nervy domain

(zMYND) motif on its carboxyl terminus. The

characteristic domain defines a ZMYNND protein

family, some of its member have been found in the

frequently affected region translocated during acute

leukemias, and were described to be transcriptional

repressors. BLU/ZMYND10 is inactivated in a

variety of human tumors due to genetic or

epigenetic mechanisms, but the function is largely

unknown. It has been reported that similar with

certain tumor suppressors, it donwregulates

JNK/MAPK signaling to exert inhibition on growth

and proliferation. ZMYND10 is implicated in the

respiratory ciliary dyskinesia.

Identity

Other names: BLU, CILD22, FLU

HGNC (Hugo): ZMYND10

Location: 3p21.31

Local order

Telomeric to NPRL2/G21, and centromeric to

RASSF1.

DNA/RNA

Note

NM_015896, 4.7 kb.

Description

The genomic size of the gene is about 4.5 kb.

The gene of 4.5-4.7 kb contains 12 (lung version, termed as canonic) or 11 (testis version) exons coding for a 2-kb, alternatively spliced mRNA, well expressed in lung and testis but not expressed in all other tested human tissues.

ZMYND10 (zinc finger, MYND-type containing 10) Zhang X, et al.


Transcription

The testis isoform contains 11 exons because of a

complex selection of an alternative acceptor site.

Pseudogene

No known pseudogenes.

Protein

Note

NP_056980; ZMYND10 (zinc finger, myeloid,

nervy and DEAF-1 (MYND)-type containing 10).

Description

The BLU protein is likely a soluble cytoplasmic

protein and shares 30-32% identity over a stretch of

100-112 amino acids (residues 334-437 or 318-430)

with proteins of the MTG/ETO family of

transcription factors and the suppressins.

The most notable feature of the protein is a C-

terminal MYND domain, spanning residues 394-

430.

The MYND domain constitutes a protein-protein

interaction surface that appears to allow these

proteins to act as transcriptional co-repressors by

association with a variety of chromatin remodelling

and transcription.

Expression

Low level expression in most human tissues.

Localisation

A majority of its coding product is located in

cytoplasma.

Function

The function of BLU/ZMYND10 is unknown. As a

MYND-containing protein BLU/ZMYND10 is

most likely to be involved in important

transcriptional regulation pathways.

It has been reported that BLU regulate cell cycle

progression through inhibition JNK signaling.

Homology

Shares 30-32% identity over a stretch of 100-112

amino acids (residues 334-437 or 318-430) with

proteins of the MTG/ETO family of transcription

factors and the suppressins.

Mutations

Note

The lung isoform is regarded as canonic isoform.

The testis-specific protein isoform contains a

different amino acid sequence between residues 199

and 234 as compared with the canonic lung-specific

isoform.

Mutation of BLU/ZMYND10 within a given

isoform is a rare event in lung cancer and other

cancers since missense changes were detected in

only 3/61 lung tumour-cell lines. The eight-gene set

in the 120-kb region show that the mutation rate

was in the range of 5%. Missense mutations were

discovered in a sample of 61 lung cancer cell lines.

It has been shown that, however, mutated

ZMYND10 protein carrying substitution of some

amino acid residues binds LRRC6 and contributes

to pathogenesis of primary ciliary dyskinesia (PCD,

or CILD22).

Somatic

Mutation carried by testis isoform 200-234:

SLSLSTLSRMLSTHNLPCLLVELLEHSPWSRR

EGG→RQWSVSQPPQLAHLKRIQRLHPVCWF

LSPG; results in the loss of one of three PKC

phosphorylation sites (residues 229-231). The

substitutions documented in PCD include:

ZMYND10, VAL16GLY, SER29PRO,

LEU39PRO, LEU266PRO, ARG369TRP,

Tyr379CYS, and ASP198GLN, ARG407GLU in

non-small cell lung cancer cells.

Implicated in

Various cancers

Note

The gene codes for the putative tumor suppressor

BLU is primarily expressed in the lung and testis,

as tissue-specific isoforms, but the level is low in

other tissues. The expression is varied in lung

cancer cells, but a non-small lung cancer line, A549

has high level of BLU. A majority of

nasopharyngeal carcinoma-derived cell lines,

however, has downregulated expression of BLU.

Mutation of the gene is relatively rare.



Hypermethylation on BLU promoter has been

detected ranging from 19% of primary non-small

cell lung cancer to 66-74% of nasopharyngeal

carcinoma (NPC).

Disease

Mutated BLU/ZMYND10 protein with several

amino acid residues substitution has been shown to

associate with LRRC6, and plays a role in the

pathogenesis of primary ciliary dyskinesia.

Hypermethylation and downregulation has been

described as a frequent event in primary tumours

such as glioma (80%), cervical squamous cell

carcinomas (77%), NPC (66%), neuroblastoma (41-

70%) and NSCLC (19-43%) with lower frequencies

observed in gallbladder carcinomas (26%),

ependymomas (13.6%) and SCLC (14%). It has

been noted that in some tumors like glioma,

methylation of BLU is an early detectable event; it

was identified in stage II glioma and stage I/II

cervical squamous cell carcinomas.

Cytogenetics

Unlike t(8;21) translocation frequently seen in acute

myelogenous leukemia, involving ZMYND motif

containing MTG8, no cytogenetic anomaly

affecting BLU has been observed in malignancies.

Hybrid/Mutated gene

No fusion gene(s) involving BLU has been

reported.

Lung cancer

Note

BLU is primarily expressed in lung and testis, with

different isoforms. The mutation is rare. The

expression is absent in a number of lung cancer cell

lines, and in 19-43% of non-small lung cancer

(NSLC) cases, BLU is silenced due to promoter

hypermethylation (Agathanggelou et al., 2003;

Marsit et al., 2005). The incidence is higher in

adenocarcinoma (AC) than in squamous cell

carcinoma (SCC). Frequent methylation for BLU

and RASSF1 has been observed but there is no

significant association. In lung cancer patients,

homozygous deletion of 3p21 region has been

association with early age of cigarette smoking

initiation.

Nasopharyngeal carcinoma (NPC)

Note

Downregulation of BLU expression was well

correlated with the promoter hypermethylation in

tumor specimens and cultured cell lines.

Methylation on BLU promoter was identified in up

to 66% of the tumors, and 6 out 7 passaged cell

lines. BLU was observed to inhibit JNK signaling

pathway, and cyclin D1 (CCND1) gene promoter

activity, arrest cell cycle at G1 phase, and block in

vitro and in vivo NPC cell growth.

Glioma

Note

BLU/ZMYND10 hypermethylation and

downregulation has been described as a frequent

event in up to 80% primary tumours of glioma.

BLU/ZMYND10 methylation is an early event

detectable in stage II glioma (Hesson et al., 2004).

In glioma tumours methylation of BLU/ZMYND10

and/or RASSF1A, located adjacent to

BLU/ZMYND10, was detected in more than 95%

(52/54) primary tumours.

Neuroblastoma

Note

Methylation leading to downregulation of BLU has

been described in up to 70% neuroblastoma (41-

70%) (Abe et al., 2005). It was shown that

methylation of promoter CGIs of RASSF1A (3p21)

and BLU (3p21) was far more frequently observed

in neuroblastomas with CpG island methylator

phenotype (CIMP).

Esophageal cancer

Note

In esophageal squamous cell carcinoma (ESCC),

BLU expression was downregulated in three out of

four Asian esophageal carcinoma cell lines, and 4

out of 8 pairs of tumor and normal tissues.

Methylation specific-PCR revealed the down-

regulation of BLU by epigenetic inactivation.

However, exogenous expression of BLU did not

functionally suppress tumorigenicity in nude mice.

These results suggest that over-expression of BLU

alone is not sufficient to inhibit tumorigenicity. (Yi

Lo et al., 2006).

Ovarian carcinoma

Note

Epithelial ovarian carcinoma is usually present at

the advanced stage, during which the patients

generally have poor prognosis. Our study aimed to

evaluate the correlation of gene methylation and the

clinical outcome of patients with advanced-stage,

high-grade ovarian serous carcinoma. The

methylation status of eight candidate genes was

first evaluated by methylation-specific PCR and

capillary electrophoresis to select three potential

genes including DAPK, CDH1, and BLU

(ZMYND10) from the exercise group of 40

patients. The methylation status of these three genes

was further investigated in the validation group

consisting of 136 patients. Patients with methylated

BLU had significantly shorter progression-free

survival (PFS; hazard ratio (HR) 1.48, 95% CI

1.01-2.56, P=0.013) and overall survival (OS; HR

1.83, 95% CI 1.07-3.11, P=0.027) in the

multivariate analysis. Methylation of BLU was also

an independent risk factor for 58 patients



undergoing optimal debulking surgery for PFS (HR

2.37, 95% CI 1.03-5.42, P=0.043) and OS (HR

3.96, 95% CI 1.45-10.81, P=0.007) in the

multivariate analysis. A possible mechanism of

BLU in chemoresistance was investigated in

ovarian cancer cell lines by in vitro apoptotic

assays. In vitro studies have shown that BLU could

upregulate the expression of BAX and enhance the

effect of paclitaxel-induced apoptosis in ovarian

cancer cells. Our study suggested that methylation

of BLU could be a potential prognostic biomarker

for advanced ovarian serous carcinoma.

Prognosis

Its correlation with prognosis of serous ovarian

carcinoma has been documented.

The methylation status of eight candidate genes,

including BLU was first evaluated by methylation-

specific PCR and capillary electrophoresis from

tumor tissues of ovarian carcinoma in a group of

patients. Patients with methylated BLU had

significantly shorter progression-free survival and

overall survival in the multivariate analysis (Chiang

et al., 2013).

Myelodysplastic syndrome (MDS)

Note

Hypermethylation in the promoter region and

downregulation at mRNA and protein levels of

BLU was detected in 34 of 79 (43%) MDS patient

samples.

There was a statistically significant difference in

methylation frequency between different refractory

anemia groups. The demethylating agent decitabine

could partly reverse hypermethylation and restore

the expression of the BLU gene. BLU promoter

hypermethylation frequently occurs in higher risk

MDS cases. BLU may play a role in the

development and etiology of MDS.

Primary ciliary dyskinesia (PCD)

Note

ZMYND10 bound to LRRC6 in HEK293T and in

human tracheal epithelial cells. These two proteins

localized to both the basal body and the striated

rootlet in Xenopus ciliated epithelial cells.

The C-terminal MYND domain of ZMYND10 was

insufficient for interaction with the CS domain of

LRRC6; but a C-terminal fragment expanding 366-

440 amino acids extending beyond the MYND

domain was necessary for interaction (see the

scheme of protein diagram).

Similar studies using progressive truncating

constructs of LRRC6 confirmed that the C-terminal

CS domain of LRRC6 is sufficient for the binding

with ZMYND10.

The protein-protein interaction is abrogated by

truncating mutations in either gene in patients with

CILD.

References LeBoeuf RD, Ban EM, Green MM, Stone AS, Propst SM, Blalock JE, Tauber JD. Molecular cloning, sequence analysis, expression, and tissue distribution of suppressin, a novel suppressor of cell cycle entry. J Biol Chem. 1998 Jan 2;273(1):361-8

Wolford JK, Prochazka M. Structure and expression of the human MTG8/ETO gene. Gene. 1998 May 28;212(1):103-9

Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res. 2000 Nov 1;60(21):6116-33

Ji L, Nishizaki M, Gao B, Burbee D, Kondo M, Kamibayashi C, Xu K, Yen N, Atkinson EN, Fang B, Lerman MI, Roth JA, Minna JD. Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo. Cancer Res. 2002 May 1;62(9):2715-20

Agathanggelou A, Dallol A, Zöchbauer-Müller S, Morrissey C, Honorio S, Hesson L, Martinsson T, Fong KM, Kuo MJ, Yuen PW, Maher ER, Minna JD, Latif F. Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers. Oncogene. 2003 Mar 13;22(10):1580-8

Liu XQ, Chen HK, Zhang XS, Pan ZG, Li A, Feng QS, Long QX, Wang XZ, Zeng YX. Alterations of BLU, a candidate tumor suppressor gene on chromosome 3p21.3, in human nasopharyngeal carcinoma. Int J Cancer. 2003 Aug 10;106(1):60-5

Hesson L, Bièche I, Krex D, Criniere E, Hoang-Xuan K, Maher ER, Latif F. Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas. Oncogene. 2004 Mar 25;23(13):2408-19

Qiu GH, Tan LK, Loh KS, Lim CY, Srivastava G, Tsai ST, Tsao SW, Tao Q. The candidate tumor suppressor gene BLU, located at the commonly deleted region 3p21.3, is an E2F-regulated, stress-responsive gene and inactivated by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma. Oncogene. 2004 Jun 10;23(27):4793-806

Abe M, Ohira M, Kaneda A, Yagi Y, Yamamoto S, Kitano Y, Takato T, Nakagawara A, Ushijima T. CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas. Cancer Res. 2005 Feb 1;65(3):828-34

Marsit CJ, Kim DH, Liu M, Hinds PW, Wiencke JK, Nelson HH, Kelsey KT. Hypermethylation of RASSF1A and BLU tumor suppressor genes in non-small cell lung cancer: implications for tobacco smoking during adolescence. Int J Cancer. 2005 Mar 20;114(2):219-23

Yi Lo PH, Chung Leung AC, Xiong W, Law S, Duh FM, Lerman MI, Stanbridge EJ, Lung ML. Expression of candidate chromosome 3p21.3 tumor suppressor genes and down-regulation of BLU in some esophageal squamous cell carcinomas. Cancer Lett. 2006 Mar 28;234(2):184-92

Riquelme E, Tang M, Baez S, Diaz A, Pruyas M, Wistuba II, Corvalan A. Frequent epigenetic inactivation of chromosome 3p candidate tumor suppressor genes in gallbladder carcinoma. Cancer Lett. 2007 May



18;250(1):100-6

Chen J, Fu L, Zhang LY, Kwong DL, Yan L, Guan XY. Tumor suppressor genes on frequently deleted chromosome 3p in nasopharyngeal carcinoma. Chin J Cancer. 2012 May;31(5):215-22

Yang Y, Zhang Q, Xu F, Wu L, He Q, Li X. Tumor suppressor gene BLU is frequently downregulated by promoter hypermethylation in myelodysplastic syndrome. J Cancer Res Clin Oncol. 2012 May;138(5):729-37

Zhang X, Liu H, Li B, Huang P, Shao J, He Z. Tumor suppressor BLU inhibits proliferation of nasopharyngeal carcinoma cells by regulation of cell cycle, c-Jun N-terminal kinase and the cyclin D1 promoter. BMC Cancer. 2012 Jun 22;12:267

Chiang YC, Chang MC, Chen PJ, Wu MM, Hsieh CY, Cheng WF, Chen CA. Epigenetic silencing of BLU through interfering apoptosis results in chemoresistance and poor prognosis of ovarian serous carcinoma patients. Endocr Relat Cancer. 2013 Apr;20(2):213-27

Park ST, Byun HJ, Kim BR, Dong SM, Park SH, Jang PR, Rho SB. Tumor suppressor BLU promotes paclitaxel antitumor activity by inducing apoptosis through the down-regulation of Bcl-2 expression in tumorigenesis. Biochem Biophys Res Commun. 2013 May 24;435(1):153-9


Zhang X, Lerman MI, He Z. ZMYND10 (zinc finger, MYND-type containing 10). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5):319-323.

Gene Section Review





ILK (integrin-linked kinase) Isabel Serrano, Paul McDonald, Shoukat Dedhar

Department of Integrative Oncology, British Columbia Cancer Research Centre of the BC Cancer

Agency, 675 West 10th Avenue, Vancouver, BC, Canada, V5Z1L3 (IS, PM, SD)

Published in Atlas Database: August 2014

Online updated version : http://AtlasGeneticsOncology.org/Genes/ILKID460ch11p15.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62119/08-2014-ILKID460ch11p15.pdf DOI: 10.4267/2042/62119


Abstract Review on ILK, with data on DNA/RNA, on the


Identity Other names: HEL-S-28, ILK-1, ILK-2, P59,

p59ILK

HGNC (Hugo): ILK

Location: 11p15.4

DNA/RNA

Description

According to Entrez-Gene, human ILK maps to

locus NC_000011.9. ILK gene contains 13 exons

and spans 9.0 kb.

Transcription

ILK encodes a predicted 451-amino acid protein

with an apparent molecular mass of 59 kD based on

SDS-PAGE.

Chromosome 11, genomic organization of human ILK. The ILK gene is located on chromosome 11 at position 15. Exactly from 6624961 bp to 6632102 bp (7142 bases) (Diagram author: Elena Serrano).

Functional domains of integrin-linked kinase (ILK). ILK is an intracellular serine/threonine protein kinase with a C-terminal kinase catalytic domain. ILK structure consists in four ankyrin repeats at the N-terminus (residues 33-164), a phosphoinositide-

binding motif and a catalytic domain (residues 180-212). The integrin-binding site is in the extreme C-terminus of the kinase domain (residues 293-451) (Diagram author: Elena Serrano).

ILK (integrin-linked kinase) Serrano I, et al.


Northern blot analysis showed that the 1.8-kb ILK

mRNA is widely expressed.

Pseudogene

An ILK pseudogene has been found in mice,

predicted gene 6263 (Gm6263).

Protein

Description

ILK is a widely expressed modular protein

composed of three major domains: an N-terminal

domain that contains four ankyrin repeats, a central

pleckstrin homology (PH)-like domain and a C-

terminal kinase domain. The N-terminal ankyrin

domain binds to PINCH (particularly interesting

new cysteinehistidine protein) - an adaptor protein

that complexes with ILK in the cytoplasm prior to

active recruitment of ILK to focal adhesion sites -

and to ILK-associated protein (ILKAP) - a protein

phosphatase 2C (PP2C)-family protein phosphatase

that negatively regulates ILK signaling (McDonald

et al., 2008a). Adjacent to the ankyrin repeats, a

sequence motif present in PH domains binds to the

second messenger PI(3,4,5)P3 and a PI3-kinase-

dependent kinase activation has been reported

(Delcommenne et al., 1998; Boulter and Van

Obberghen-Schilling, 2006). The C-terminus kinase

domain also interacts with integrins, as well as with

the focal adhesion proteins paxillin (Nikolopoulos

and Turner, 2001; Nikolopoulos and Turner, 2002)

and parvins (Hannigan et al., 2005; Legate et al.,

2006), which link ILK, and therefore integrins, to

the actin cytoskeleton.

Expression

ILK is ubiquitously expressed in most tissues, with

predominance at skeletal muscle, heart, kidney and

pancreas. Increased expression of ILK is correlated

with progression of several tumor types,

constituting an attractive therapeutic target in

human cancer.

Localisation

ILK is generally considered a cytosolic protein

localized at focal adhesions, however ILK co-

localizes with tubulins and many centrosomal and

mitotic spindle associated proteins at centrosomes.

Function

Integrin-linked kinase (ILK) (Hannigan et al., 1996)

is a multifunctional protein kinase which is

implicated in a large number of cellular processes

and diseases, participating in signal transduction

pathways that control cell survival, differentiation,

proliferation and gene expression in mammalian

cells (Wu, 2001). ILK, PINCH1 and α-parvin form

a ternary complex termed IPP (ILK-PINCH-parvin)

that localizes to both focal adhesions (FAs) and

fibrillar adhesions (FBs) and is essential for several

integrin-dependent functions. The IPP complex,

interacts with the cytoplasmic tail of β integrins,

resulting in the engagement and organization of the

cytoskeleton as well as activation of signalling

pathways. Deletion of the genes encoding ILK or

PINCH1 similarly blocks maturation of FAs and

FBs by downregulating expression or recruitment

of tensin and destabilizing α5β1-integrin-

cytoskeleton linkages (Legate et al., 2006; Stanchi

et al., 2009; Elad et al., 2013). The kinase activity

of ILK is stimulated by integrins and soluble

mediators, including growth factors and

chemokines, and is regulated in a phosphoinositide

3-kinase (PI3K)-dependent manner. The activity of

ILK is antagonized by phosphatases such as ILKAP

and phosphatase and tensin homolog deleted on

chromosome 10 (PTEN) (McDonald et al., 2008a).

Important downstream targets of ILK signaling

include PKB/Akt, GSK-3, β-catenin, p44/p42 MAP

kinases, the myosin light chain (MLC) (Hannigan et

al., 2011) and the Hippo pathway through Merlin's

phosphatase MYPT1 (Serrano et al., 2013c). AKT

is a regulator of cell survival and apoptosis. To

become fully activated, PKB/Akt requires

phosphorylation at two sites, threonine 308 and

serine 473. Phosphorylation at serine 473 depends

on PI3K activity (Persad et al., 2001), the rictor-

mTOR complex (Sarbassov et al., 2005) and the

ILK-Rictor complex (McDonald et al., 2008b).

GSK-3 is phosphorylated and inactivated at serine 9

by ILK, regulating the cell cycle through

proteolysis of cyclin D1 and activation of the

transcription factor AP1 (Troussard et al., 1999).

Inactivation of GSK-3 stabilizes β-catenin, whose

accumulation is related to deregulation of

proliferation, migration and differentiation (Oloumi

et al., 2004). ILK can directly phosphorylate MLC

on Ser18/thr19 influencing in cell contraction,

motility and migration (Deng et al., 2001). ILK

function is required in TGFβ-1-induced EMT in

mammary epithelial cells, and the ILK/Rictor

complex has been identified as a potential

molecular target for preventing/reversing EMT

(Serrano et al., 2013b). But ILK can also directly

regulate EMT by promoting the expression of Snail

transcriptionally (McPhee et al., 2008) and via

posttranslational modification through GSK-3b.

ILK also localize to centrosomes, where it is

recruited by RUVBI1/2, and it regulates mitotic

spindle assembly by promoting Aurora A

kinase/TACC3/ch-TOG interactions (Fielding et al.,

2008) as well as centrosome clustering through the

microtubule regulating proteins TACC3 and ch-

TOG (Fielding et al., 2011). In addition, ILK

regulates microtubule dynamics since

overexpression of ILK in HeLa cells is associated

with a shorter duration of mitosis and decreased

sensitivity to paclitaxel, a chemotherapeutic agent

that suppresses microtubule dynamics and



ILK interaction partners. Schematic representation of the signal transduction pathways where ILK is implicated. Dark green represents direct interaction, red represents indirect interaction and light brown represents not analysed. Adapted from Widmaier

et al., 2012 by Elena Serrano.

conversely, the use of a small molecule inhibitor

selective against ILK, QLT-0267, results in

suppressed microtubule dynamics (Lim et al.,

2013). ILK regulation of microtubules is critical for

proper trafficking of caveolin-1-containing vesicles.

ILK controls this process by regulating microtubule

stability through the recruitment of the scaffold

protein IQGAP1 and its downstream effector

mDia1 to nascent, cortical adhesion sites. In the

absence of ILK, caveolae remain associated with

dynamic microtubules, fail to stably fuse with the

plasma membrane, and subsequently accumulate in

intracellular structures (Wickström et al., 2010).

Homology

The ILK gene is highly conserved in a total of 24

species. The most representatives are human,

mouse, chicken, lizard, African clawed frog,

zebrafish, fruit fly, worm.

Mutations 1. ILK mutation causes human cardiomyopathy via

simultaneous defects in cardiomyocytes and

endothelial cells (Knoll et al., 2007).

2. Embryonic lethality was observed in Xenopus

laevis (Yasunaga et al., 2005) and mouse (Sakai et

al., 2003) models of ILK ablation, and this was

attributed to defects in adhesive and migratory

mechanics.

Implicated in

Melanoma

Increased expression of integrin-linked kinase is

correlated with melanoma progression and poor

patient survival (Dai et al., 2003; Wong et al.,

2007). ILK regulates melanoma angiogenesis by



activating NF-kB/interleukin-6 signaling pathway

(Wani et al., 2011).

Colon cancer

ILK is hyperexpressed in malignant crypts from

both the primary and metastatic lesions. Changes in

ILK activity coincide with changes on downstream

targets, primarily GSK3β. Dysregulation of the

ILK-signaling nexus is an important early event in

the genesis of human colon cancer (Marotta et al.,

2003). ILK expression levels correlated with tumor

invasion, grade and stage; higher levels in

metastatic tumors (Bravou et al., 2003). Thymosin

beta 4 induces colon cancer cell migration and

clinical metastasis via enhancing

ILK/IQGAP1/Rac1 signal transduction pathway

(Tang et al., 2011).

Gastric cancer

ILK might be a novel molecular marker for

aggressive gastric cancer. Strong expression of ILK

is observed in the majority of primary tumors that

were associated with tumor cell invasion and nodal

metastasis; no expression in non-neoplastic gastric

epithelia (Ito et al., 2003). ILK might be used as a

potential therapeutic strategy to combat multi-drug

resistance through blocking PI3K-Akt and MAPK-

ERK pathways in human gastric carcinoma (Song

et al., 2012).

Lung cancer

ILK expression is significantly associated with

tumor grade and stage, and lower than 5-year

survival. Increased expression of ILK is a poor

prognostic factor in patients with non-small cell

lung cancer (Takanami 2005; Okamura et al.,

2007).

Anaplastic thyroid cancer

ILK is a potential therapeutic target for treating

anaplastic thyroid cancer. ILK expression and

activity are elevated in human anaplastic thyroid

cancer and ILK inhibition leads to growth arrest

and apoptosis in vitro and in vivo (Younes et al.,

2005).

Squamous cell carcinoma of head and neck

ILK is overexpressed in SCCHN tumor specimens.

Targeting ILK with the small-molecule ILK

inhibitor QLT0267 inhibits cell growth and induces

apoptosis in SCCHN cell lines by reducing ILK

activity and Akt phosphorylation (Younes et al.,

2007).

Pancreatic cancer

ILK is involved with aggressive capability in

pancreatic cancer. Significant association between

strong expression of ILK and poor prognosis of

pancreatic cancer patients has been observed

(Sawai et al., 2006). Silencing ILK could be a

potentially useful therapeutic approach for treating

pancreatic cancer (Schaeffer et al., 2010; Zhu et al.,

2012).

Ovarian cancer

ILK expression is increased with tumor

progression; normal epithelium was negative for

ILK (Ahmed et al., 2003). ILK gene silencing

suppresses tumor growth in human ovarian

carcinoma HO-8910 xenografts in mice (Li et al.,

2013) and induces apoptosis in ovarian carcinoma

SKOV3 cell (Liu et al., 2012).

Prostate cancer

ILK expression is increased with tumor

progression. Increased expression of the protein has

been demonstrated to be inversely related to the 5-

year survival rate in prostate cancer (Graff et al.,

2001). ILK stimulates the expression of VEGF by

stimulating HIF-1alpha protein expression in a

PKB/Akt- and mTOR/FRAP-dependent manner

and knockdown of ILK expression with siRNA, or

inhibition of ILK activity, results in significant

inhibition of HIF-1alpha and VEGF expression

(Tan el al., 2004). Compound 22, a novel ILK

inhibitor, exhibited high in vitro potency against a

panel of prostate and breast cancer cell lines and its

therapeutic potential has been suggested by its in

vivo efficacy as a single oral agent in suppressing

PC-3 xenograft tumor growth (Lee et al., 2011).

Mesothelioma

ILK is expressed in malignant mesothelioma.

Normal mesothelial cells and lung parenchyma are

negative (Watzka et al., 2008). Evaluating ILK's

potential use as a marker of disease progression in

malignant pleural mesothelioma has been suggested

(Watzka et al., 2013).

Ewing's sarcoma and primitive neuroectodermal tumor

Expression is observed (Chung et al., 1998).

Glioblastoma

The ILK inhibitor, QLT0267, was able to reduce

cellular invasion and angiogenesis of glioma cells.

Blocking the ILK/Akt pathway is a potential

strategy for molecular targeted therapy for gliomas

(Kou et al., 2005; Edwards et al., 2008). Expression

of insulin-like growth factor-binding protein 2

(IGFBP2), a glioma oncogene emerging as a target

for therapeutic intervention, requires ILK to induce

cell motility and activate NF-kB (Holmes et al.,

2012).

Musculoskeletal sarcoma

Prognostic factor in osteosarcoma and a novel

potential therapeutic target for the treatment of

osteosarcoma (Rhee et al., 2013).



Medulloblastoma

Expression is observed (Chung et al., 1998).

Breast cancer, cancer cell growth and metastasis

Epithelial to mesenchymal transition (EMT) causes

fibrosis, cancer progression and metastasis.

Acquisition of invasive and migratory

characteristics in cancer cells results primarily from

adopting an EMT phenotype. Overexpression of

ILK induces EMT in mammary epithelial cells

(Somasiri et al., 2001) and targeting this signaling

cascade is an effective strategy for the treatment of

fibrotic kidney (Li et al., 2009), lung (Kavvadas et

al., 2010) or bladder cancer (Matsui et al., 2011).

ILK is a key intracellular mediator of TGFβ-1

induced EMT (Li et al., 2009) through a Snail and

Slug mechanism (Serrano et al., 2013b). TGFβ-1

mediated EMT induces an interaction between ILK

and Rictor and disruption of this interaction by

silencing ILK or using ILK inhibitor molecule,

QLT0267, blocks TGFβ-1 induced EMT and

partially reverses the mesenchymal phenotype in

breast cancer cell lines (Serrano et al., 2013b). ILK

promotes lung cancer cell migration and invasion

through the induction of EMT process (Chen et al.,

2013) and is a therapeutically targetable mediator of

ERG-induced EMT and transformation in prostate

cancer (Becker-Santos et al., 2012) and in high

glucose-induced epithelial-mesenchymal transition

of renal tubular cell (Peng et al., 2012). A

significant acceleration in mammary tumor

incidence and growth was observed in the MMTV-

Wnt/ILK mice compared to Wnt alone, showing the

cooperation between Wnt1 and ILK transgenes

during mammary carcinogenesis (Oloumi et al.,

2010). Furthermore, mammary epithelial disruption

of ILK in mice results in a profound block in

mammary tumor induction (Pontier et al., 2010).

ILK plays a critical role in the suppression of the

Hippo pathway in breast, colon and prostate cancer

cells; inactivation of ILK suppresses YAP

activation and tumour growth in vivo (Serrano et

al., 2013c). Expression of LIMD2 is associated with

the metastatic process of papillary thyroid

carcinoma (Cerutti et al., 2007) and has been

described to bound directly to the kinase domain of

ILK in IPP, a signal transduction pathway strongly

linked to cell motility and invasion suggesting that

LIMD2 potentiates ILK biological effects (Peng et

al., 2014).

Embryonic development

Embryonic lethality was observed in Xenopus

laevis (Yasunaga et al., 2005) and mouse (Sakai et

al., 2003) models of ILK ablation, and this was

attributed to defects in adhesive and migratory

mechanics.

Musculoskeletal system and skin

Note

During bone formation, ILK-dependent interactions

and downstream signaling effectors are required for

proliferation and differentiation of chondrocytes

within the growth plate. The kinase activity of ILK

is necessary for mechanosensing and signaling in

vertebrate skeletal muscle (Postel et al., 2008). ILK

is important for proliferation, adhesion, spreading

and migration of keratinocytes (Lorenz et al., 2007;

Nakrieko et al., 2008). ILK plays an important

modulatory role in the normal contribution of hair

follicle stem cell progeny to the regenerating

epidermis following injury (Nakrieko et al., 2011).

ILK and PI3K activation after skin wounding are

critical for tissue repair in an HGF-dependent

mechanism (Serrano et al., 2012).

Disease

Mice with depletion of ILK in chondrocytes suffer

from dwarfism and chondrodysplasia (Grashoff et

al., 2003; Terpstra et al., 2003). Lack of ILK in skin

causes skin blistering and inhibition of hair follicle

development (Lorenz et al., 2007; Nakrieko et al.,

2008). ILK deficiency in mice leads to retarded

wound closure in skin (Serrano et al., 2012).

Central nervous system

Note

The downregulation of ILK expression was found

to inhibit axon formation through the elimination or

length reduction of the axon. ILK-Akt-GSK3

signaling axis is implicated in the development and

function of neurons (Guo et al., 2007).

Disease

ILK deletion in the central nervous system leads to

Cobblestone lissencephaly (Niewmierzycka et al.,

2005) and to cerebellar development and loss of

NGF signaling (Mills et al., 2006).

Kidney

Note

ILK function is required for epithelial to

mesenchymal transition and adhesion and in the

maintenance of glomerular filtration barrier. Human

mesangial cells exposed to abnormal collagen I are

protected against apoptosis by a complex

mechanism involving integrin β1/ILK/AKT-

dependent NFkB activation with consequent Bcl-xL

overexpression, that opposes a simultaneously

activated ILK/GSK-3β-dependent Bim expression

and this dual mechanism may play a role in the

progression of glomerular dysfunction (del Nogal et

al., 2012). ILK plays a key role in the regulation of

renal inflammation by modulating the canonical

NF-kB pathway, and suggest a potential therapeutic

target for inflammatory renal diseases (Alique et al.,

2014).



ILK regulates expression of tubular water channel

aquaporin-2 (AQP2) and its apical membrane

presence in the renal tubule, polyuria and decreased

urine osmolality were present in ILK conditional-

knockdown (cKD-ILK) adult mice compared with

nondepleted ILK littermates pointing ILK as a

therapeutic target in nephrogenic diabetes insipidus

(Cano-Penalver et al., 2014).

Disease

Fibrosis; proteinuria (Dai et al., 2006; El-Aouni et

al., 2006).

Heart

Note

ILK plays a central role in protecting the

mammalian heart against cardiomyopathy and

failure. Thymosin beta4 activates ILK and

promotes cardiac cell function and regeneration

after infarction (Bock-Marquette et al., 2004;

Srivastava et al., 2007). The heart uses the Integrin-

ILK-beta-parvin network to sense mechanical

stretch (Bendig et al., 2006). Deletion of ILK

results in disaggregation of cardiomyocytes,

associated with disruption of adhesion signaling

through the beta1-integrin/FAK (focal adhesion

kinase) complex (White et al., 2006). ILK is

implicated in cardiac hypertrophy and contractility

and is a novel cardiotropic factor that promotes

recruitment of human fetal heart cells to a

cardiomyogenic fate (Traister et al., 2012).

Increased expression of integrin-linked kinase

improves cardiac function and decreases mortality

in dilated cardiomyopathy model of rats (Gu et al.,

2012). In Drosophila, severely compromised

integrin/ILK pathway function is detrimental for the

heart, but fine-tuned moderate reduction maintains

youthful cardiac performance, suggesting a dual

role for this complex in regulating cardiac integrity

and aging (Nishimura et al., 2014).

Disease

Cardiomyogenesis

Blood vessels

Note

ILK closely regulates capillary formation and the

survival of progenitor and differentiated endothelial

cells. In endothelial cells, VEGF stimulates ILK

activity, and inhibition of ILK expression or

activity results in the inhibition of VEGF-mediated

endothelial cell migration, capillary formation in

vitro, and angiogenesis in vivo (Tan et al., 2004).

ILK controls postnatal vasculogenesis by

recruitment of endothelial progenitor cells to

ischemic tissue (Lee et al., 2006). ILK acts as a

regulatory partner of eNOS in vivo that prevents

eNOS uncoupling, and suggest ILK as a therapeutic

target for prevention of endothelial dysfunction

related to shear stress-induced vascular diseases

(Herranz et al., 2012). ILK regulates retinal

vascular endothelial proliferation, migration and

tube formation and targeting ILK may be a

potentially useful therapeutic approach for treating

ocular neovascularization (Xie et al., 2013).

Deletion of ILK in mice leads to increased vascular

content and increased activity of sGC (soluble

Guanylyl Cyclase) and PKG (Protein Kinase G),

resulting in a more intense vasodilatory response to

nitric oxide donors (Serrano et al., 2013a).

Disease

Tumor angiogenesis (Tan et al., 2004).

References Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature. 1996 Jan 4;379(6560):91-6

Chung DH, Lee JI, Kook MC, Kim JR, Kim SH, Choi EY, Park SH, Song HG. ILK (beta1-integrin-linked protein kinase): a novel immunohistochemical marker for Ewing's sarcoma and primitive neuroectodermal tumour. Virchows Arch. 1998 Aug;433(2):113-7

Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11211-6

Troussard AA, Tan C, Yoganathan TN, Dedhar S. Cell-extracellular matrix interactions stimulate the AP-1 transcription factor in an integrin-linked kinase- and glycogen synthase kinase 3-dependent manner. Mol Cell Biol. 1999 Nov;19(11):7420-7

Deng JT, Van Lierop JE, Sutherland C, Walsh MP. Ca2+-independent smooth muscle contraction. a novel function for integrin-linked kinase. J Biol Chem. 2001 May 11;276(19):16365-73

Graff JR, Deddens JA, Konicek BW, Colligan BM, Hurst BM, Carter HW, Carter JH. Integrin-linked kinase expression increases with prostate tumor grade. Clin Cancer Res. 2001 Jul;7(7):1987-91

Nikolopoulos SN, Turner CE. Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions. J Biol Chem. 2001 Jun 29;276(26):23499-505

Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D, Yan J, Sanghera J, Walsh MP, Dedhar S. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J Biol Chem. 2001 Jul 20;276(29):27462-9

Somasiri A, Howarth A, Goswami D, Dedhar S, Roskelley CD. Overexpression of the integrin-linked kinase mesenchymally transforms mammary epithelial cells. J Cell Sci. 2001 Mar;114(Pt 6):1125-36

Wu C. ILK interactions. J Cell Sci. 2001 Jul;114(Pt 14):2549-50

Nikolopoulos SN, Turner CE. Molecular dissection of actopaxin-integrin-linked kinase-Paxillin interactions and their role in subcellular localization. J Biol Chem. 2002 Jan 11;277(2):1568-75



Ahmed N, Riley C, Oliva K, Stutt E, Rice GE, Quinn MA. Integrin-linked kinase expression increases with ovarian tumour grade and is sustained by peritoneal tumour fluid. J Pathol. 2003 Oct;201(2):229-37

Bravou V, Klironomos G, Papadaki E, Stefanou D, Varakis J. Integrin-linked kinase (ILK) expression in human colon cancer. Br J Cancer. 2003 Dec 15;89(12):2340-1

Dai DL, Makretsov N, Campos EI, Huang C, Zhou Y, Huntsman D, Martinka M, Li G. Increased expression of integrin-linked kinase is correlated with melanoma progression and poor patient survival. Clin Cancer Res. 2003 Oct 1;9(12):4409-14

Grashoff C, Aszódi A, Sakai T, Hunziker EB, Fässler R. Integrin-linked kinase regulates chondrocyte shape and proliferation. EMBO Rep. 2003 Apr;4(4):432-8

Ito R, Oue N, Zhu X, Yoshida K, Nakayama H, Yokozaki H, Yasui W. Expression of integrin-linked kinase is closely correlated with invasion and metastasis of gastric carcinoma. Virchows Arch. 2003 Feb;442(2):118-23

Marotta A, Parhar K, Owen D, Dedhar S, Salh B. Characterisation of integrin-linked kinase signalling in sporadic human colon cancer. Br J Cancer. 2003 Jun 2;88(11):1755-62

Sakai T, Li S, Docheva D, Grashoff C, Sakai K, Kostka G, Braun A, Pfeifer A, Yurchenco PD, Fässler R. Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation. Genes Dev. 2003 Apr 1;17(7):926-40

Terpstra L, Prud'homme J, Arabian A, Takeda S, Karsenty G, Dedhar S, St-Arnaud R. Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes. J Cell Biol. 2003 Jul 7;162(1):139-48

Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D. Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature. 2004 Nov 25;432(7016):466-72

Oloumi A, McPhee T, Dedhar S. Regulation of E-cadherin expression and beta-catenin/Tcf transcriptional activity by the integrin-linked kinase. Biochim Biophys Acta. 2004 Apr 1;1691(1):1-15

Tan C, Cruet-Hennequart S, Troussard A, Fazli L, Costello P, Sutton K, Wheeler J, Gleave M, Sanghera J, Dedhar S. Regulation of tumor angiogenesis by integrin-linked kinase (ILK). Cancer Cell. 2004 Jan;5(1):79-90

Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005 Jan;5(1):51-63

Koul D, Shen R, Bergh S, Lu Y, de Groot JF, Liu TJ, Mills GB, Yung WK. Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma. Mol Cancer Ther. 2005 Nov;4(11):1681-8

Niewmierzycka A, Mills J, St-Arnaud R, Dedhar S, Reichardt LF. Integrin-linked kinase deletion from mouse cortex results in cortical lamination defects resembling cobblestone lissencephaly. J Neurosci. 2005 Jul 27;25(30):7022-31

Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005 Feb 18;307(5712):1098-101

Takanami I. Increased expression of integrin-linked kinase is associated with shorter survival in non-small cell lung cancer. BMC Cancer. 2005 Jan 5;5:1

Yasunaga T, Kusakabe M, Yamanaka H, Hanafusa H, Masuyama N, Nishida E. Xenopus ILK (integrin-linked kinase) is required for morphogenetic movements during gastrulation. Genes Cells. 2005 Apr;10(4):369-79

Younes MN, Kim S, Yigitbasi OG, Mandal M, Jasser SA, Dakak Yazici Y, Schiff BA, El-Naggar A, Bekele BN, Mills GB, Myers JN. Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. Mol Cancer Ther. 2005 Aug;4(8):1146-56

Bendig G, Grimmler M, Huttner IG, Wessels G, Dahme T, Just S, Trano N, Katus HA, Fishman MC, Rottbauer W. Integrin-linked kinase, a novel component of the cardiac mechanical stretch sensor, controls contractility in the zebrafish heart. Genes Dev. 2006 Sep 1;20(17):2361-72

Boulter E, Van Obberghen-Schilling E. Integrin-linked kinase and its partners: a modular platform regulating cell-matrix adhesion dynamics and cytoskeletal organization. Eur J Cell Biol. 2006 Apr;85(3-4):255-63

Dai C, Stolz DB, Bastacky SI, St-Arnaud R, Wu C, Dedhar S, Liu Y. Essential role of integrin-linked kinase in podocyte biology: Bridging the integrin and slit diaphragm signaling. J Am Soc Nephrol. 2006 Aug;17(8):2164-75

El-Aouni C, Herbach N, Blattner SM, Henger A, Rastaldi MP, Jarad G, Miner JH, Moeller MJ, St-Arnaud R, Dedhar S, Holzman LB, Wanke R, Kretzler M. Podocyte-specific deletion of integrin-linked kinase results in severe glomerular basement membrane alterations and progressive glomerulosclerosis. J Am Soc Nephrol. 2006 May;17(5):1334-44

Lee SP, Youn SW, Cho HJ, Li L, Kim TY, Yook HS, Chung JW, Hur J, Yoon CH, Park KW, Oh BH, Park YB, Kim HS. Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue. Circulation. 2006 Jul 11;114(2):150-9

Legate KR, Montañez E, Kudlacek O, Fässler R. ILK, PINCH and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell Biol. 2006 Jan;7(1):20-31

Mills J, Niewmierzycka A, Oloumi A, Rico B, St-Arnaud R, Mackenzie IR, Mawji NM, Wilson J, Reichardt LF, Dedhar S. Critical role of integrin-linked kinase in granule cell precursor proliferation and cerebellar development. J Neurosci. 2006 Jan 18;26(3):830-40

Sawai H, Okada Y, Funahashi H, Matsuo Y, Takahashi H, Takeyama H, Manabe T. Integrin-linked kinase activity is associated with interleukin-1 alpha-induced progressive behavior of pancreatic cancer and poor patient survival. Oncogene. 2006 Jun 1;25(23):3237-46

White DE, Coutu P, Shi YF, Tardif JC, Nattel S, St Arnaud R, Dedhar S, Muller WJ. Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure. Genes Dev. 2006 Sep 1;20(17):2355-60

Cerutti JM, Oler G, Michaluart P Jr, Delcelo R, Beaty RM, Shoemaker J, Riggins GJ. Molecular profiling of matched samples identifies biomarkers of papillary thyroid carcinoma lymph node metastasis. Cancer Res. 2007 Aug 15;67(16):7885-92

Guo W, Jiang H, Gray V, Dedhar S, Rao Y. Role of the



integrin-linked kinase (ILK) in determining neuronal polarity. Dev Biol. 2007 Jun 15;306(2):457-68

Knöll R, Postel R, Wang J, Krätzner R, Hennecke G, Vacaru AM, Vakeel P, Schubert C, Murthy K, Rana BK, Kube D, Knöll G, Schäfer K, Hayashi T, Holm T, Kimura A, Schork N, Toliat MR, Nürnberg P, Schultheiss HP, Schaper W, Schaper J, Bos E, Den Hertog J, van Eeden FJ, Peters PJ, Hasenfuss G, Chien KR, Bakkers J. Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation. 2007 Jul 31;116(5):515-25

Lorenz K, Grashoff C, Torka R, Sakai T, Langbein L, Bloch W, Aumailley M, Fässler R. Integrin-linked kinase is required for epidermal and hair follicle morphogenesis. J Cell Biol. 2007 May 7;177(3):501-13

Okamura M, Yamaji S, Nagashima Y, Nishikawa M, Yoshimoto N, Kido Y, Iemoto Y, Aoki I, Ishigatsubo Y. Prognostic value of integrin beta1-ILK-pAkt signaling pathway in non-small cell lung cancer. Hum Pathol. 2007 Jul;38(7):1081-91

Srivastava D, Saxena A, Michael Dimaio J, Bock-Marquette I. Thymosin beta4 is cardioprotective after myocardial infarction. Ann N Y Acad Sci. 2007 Sep;1112:161-70

Wong RP, Ng P, Dedhar S, Li G. The role of integrin-linked kinase in melanoma cell migration, invasion, and tumor growth. Mol Cancer Ther. 2007 Jun;6(6):1692-700

Younes MN, Yigitbasi OG, Yazici YD, Jasser SA, Bucana CD, El-Naggar AK, Mills GB, Myers JN. Effects of the integrin-linked kinase inhibitor QLT0267 on squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 2007 Jan;133(1):15-23

Edwards LA, Woo J, Huxham LA, Verreault M, Dragowska WH, Chiu G, Rajput A, Kyle AH, Kalra J, Yapp D, Yan H, Minchinton AI, Huntsman D, Daynard T, Waterhouse DN, Thiessen B, Dedhar S, Bally MB. Suppression of VEGF secretion and changes in glioblastoma multiforme microenvironment by inhibition of integrin-linked kinase (ILK). Mol Cancer Ther. 2008 Jan;7(1):59-70

Fielding AB, Dobreva I, Dedhar S. Beyond focal adhesions: integrin-linked kinase associates with tubulin and regulates mitotic spindle organization. Cell Cycle. 2008 Jul 1;7(13):1899-906

McDonald PC, Fielding AB, Dedhar S. Integrin-linked kinase--essential roles in physiology and cancer biology. J Cell Sci. 2008a Oct 1;121(Pt 19):3121-32

McDonald PC, Oloumi A, Mills J, Dobreva I, Maidan M, Gray V, Wederell ED, Bally MB, Foster LJ, Dedhar S. Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res. 2008b Mar 15;68(6):1618-24

McPhee TR, McDonald PC, Oloumi A, Dedhar S. Integrin-linked kinase regulates E-cadherin expression through PARP-1. Dev Dyn. 2008 Oct;237(10):2737-47

Nakrieko KA, Welch I, Dupuis H, Bryce D, Pajak A, St Arnaud R, Dedhar S, D'Souza SJ, Dagnino L. Impaired hair follicle morphogenesis and polarized keratinocyte movement upon conditional inactivation of integrin-linked kinase in the epidermis. Mol Biol Cell. 2008 Apr;19(4):1462-73

Postel R, Vakeel P, Topczewski J, Knöll R, Bakkers J. Zebrafish integrin-linked kinase is required in skeletal muscles for strengthening the integrin-ECM adhesion complex. Dev Biol. 2008 Jun 1;318(1):92-101

Watzka SB, Setinek U, Huber M, Cantonati H, Lax F, Watson S, Weigel G, Müller MR. Reactivity of integrin-linked kinase in human mesothelial cell proliferation. Interact Cardiovasc Thorac Surg. 2008 Feb;7(1):107-10

Li Y, Tan X, Dai C, Stolz DB, Wang D, Liu Y. Inhibition of integrin-linked kinase attenuates renal interstitial fibrosis. J Am Soc Nephrol. 2009 Sep;20(9):1907-18

Stanchi F, Grashoff C, Nguemeni Yonga CF, Grall D, Fässler R, Van Obberghen-Schilling E. Molecular dissection of the ILK-PINCH-parvin triad reveals a fundamental role for the ILK kinase domain in the late stages of focal-adhesion maturation. J Cell Sci. 2009 Jun 1;122(Pt 11):1800-11

Kavvadas P, Kypreou KP, Protopapadakis E, Prodromidi E, Sideras P, Charonis AS. Integrin-linked kinase (ILK) in pulmonary fibrosis. Virchows Arch. 2010 Nov;457(5):563-75

Oloumi A, Maidan M, Lock FE, Tearle H, McKinney S, Muller WJ, Aparicio SA, Dedhar S. Cooperative signaling between Wnt1 and integrin-linked kinase induces accelerated breast tumor development. Breast Cancer Res. 2010;12(3):R38

Pontier SM, Huck L, White DE, Rayment J, Sanguin-Gendreau V, Hennessy B, Zuo D, St-Arnaud R, Mills GB, Dedhar S, Marshall CJ, Muller WJ. Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer. Oncogene. 2010 Jun 10;29(23):3374-85

Schaeffer DF, Assi K, Chan K, Buczkowski AK, Chung SW, Scudamore CH, Weiss A, Salh B, Owen DA. Tumor expression of integrin-linked kinase (ILK) correlates with the expression of the E-cadherin repressor snail: an immunohistochemical study in ductal pancreatic adenocarcinoma. Virchows Arch. 2010 Mar;456(3):261-8

Wickström SA, Lange A, Hess MW, Polleux J, Spatz JP, Krüger M, Pfaller K, Lambacher A, Bloch W, Mann M, Huber LA, Fässler R. Integrin-linked kinase controls microtubule dynamics required for plasma membrane targeting of caveolae. Dev Cell. 2010 Oct 19;19(4):574-88

Fielding AB, Lim S, Montgomery K, Dobreva I, Dedhar S. A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells. Oncogene. 2011 Feb 3;30(5):521-34

Hannigan GE, McDonald PC, Walsh MP, Dedhar S. Integrin-linked kinase: not so 'pseudo' after all. Oncogene. 2011 Oct 27;30(43):4375-85

Lee SL, Hsu EC, Chou CC, Chuang HC, Bai LY, Kulp SK, Chen CS. Identification and characterization of a novel integrin-linked kinase inhibitor. J Med Chem. 2011 Sep 22;54(18):6364-74

Nakrieko KA, Rudkouskaya A, Irvine TS, D'Souza SJ, Dagnino L. Targeted inactivation of integrin-linked kinase in hair follicle stem cells reveals an important modulatory role in skin repair after injury. Mol Biol Cell. 2011 Jul 15;22(14):2532-40

Tang MC, Chan LC, Yeh YC, Chen CY, Chou TY, Wang WS, Su Y. Thymosin beta 4 induces colon cancer cell migration and clinical metastasis via enhancing ILK/IQGAP1/Rac1 signal transduction pathway. Cancer Lett. 2011 Sep 28;308(2):162-71

Wani AA, Jafarnejad SM, Zhou J, Li G. Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway. Oncogene. 2011 Jun 16;30(24):2778-88



Becker-Santos DD, Guo Y, Ghaffari M, Vickers ED, Lehman M, Altamirano-Dimas M, Oloumi A, Furukawa J, Sharma M, Wang Y, Dedhar S, Cox ME. Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models. Carcinogenesis. 2012 Dec;33(12):2558-67

del Nogal M, Luengo A, Olmos G, Lasa M, Rodriguez-Puyol D, Rodriguez-Puyol M, Calleros L. Balance between apoptosis or survival induced by changes in extracellular-matrix composition in human mesangial cells: a key role for ILK-NFκB pathway. Apoptosis. 2012 Dec;17(12):1261-74

Gu R, Bai J, Ling L, Ding L, Zhang N, Ye J, Ferro A, Xu B. Increased expression of integrin-linked kinase improves cardiac function and decreases mortality in dilated cardiomyopathy model of rats. PLoS One. 2012;7(2):e31279

Herranz B, Marquez S, Guijarro B, Aracil E, Aicart-Ramos C, Rodriguez-Crespo I, Serrano I, Rodríguez-Puyol M, Zaragoza C, Saura M. Integrin-linked kinase regulates vasomotor function by preventing endothelial nitric oxide synthase uncoupling: role in atherosclerosis. Circ Res. 2012 Feb 3;110(3):439-49

Holmes KM, Annala M, Chua CY, Dunlap SM, Liu Y, Hugen N, Moore LM, Cogdell D, Hu L, Nykter M, Hess K, Fuller GN, Zhang W. Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-κB network. Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3475-80

Liu Q, Xiao L, Yuan D, Shi X, Li P. Silencing of the integrin-linked kinase gene induces the apoptosis in ovarian carcinoma. J Recept Signal Transduct Res. 2012 Apr;32(2):120-7

Matsui Y, Assi K, Ogawa O, Raven PA, Dedhar S, Gleave ME, Salh B, So AI. The importance of integrin-linked kinase in the regulation of bladder cancer invasion. Int J Cancer. 2012 Feb 1;130(3):521-31

Peng L, Yang J, Ning C, Zhang J, Xiao X, He D, Wang X, Li Z, Fu S, Ning J. Rhein inhibits integrin-linked kinase expression and regulates matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio in high glucose-induced epithelial-mesenchymal transition of renal tubular cell. Biol Pharm Bull. 2012;35(10):1676-85

Serrano I, Díez-Marqués ML, Rodríguez-Puyol M, Herrero-Fresneda I, Raimundo García del M, Dedhar S, Ruiz-Torres MP, Rodríguez-Puyol D. Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF). Exp Cell Res. 2012 Nov 15;318(19):2470-81

Song W, Jiang R, Zhao CM. Role of integrin-linked kinase in multi-drug resistance of human gastric carcinoma SGC7901/DDP cells. Asian Pac J Cancer Prev. 2012;13(11):5619-25

Traister A, Aafaqi S, Masse S, Dai X, Li M, Hinek A, Nanthakumar K, Hannigan G, Coles JG. ILK induces cardiomyogenesis in the human heart. PLoS One. 2012;7(5):e37802

Widmaier M, Rognoni E, Radovanac K, Azimifar SB, Fässler R. Integrin-linked kinase at a glance. J Cell Sci. 2012 Apr 15;125(Pt 8):1839-43

Zhu XY, Liu N, Liu W, Song SW, Guo KJ. Silencing of the integrin-linked kinase gene suppresses the proliferation, migration and invasion of pancreatic cancer cells (Panc-1).

Genet Mol Biol. 2012 Apr;35(2):538-44

Chen D, Zhang Y, Zhang X, Li J, Han B, Liu S, Wang L, Ling Y, Mao S, Wang X. Overexpression of integrin-linked kinase correlates with malignant phenotype in non-small cell lung cancer and promotes lung cancer cell invasion and migration via regulating epithelial-mesenchymal transition (EMT)-related genes. Acta Histochem. 2013 Mar;115(2):128-36

Elad N, Volberg T, Patla I, Hirschfeld-Warneken V, Grashoff C, Spatz JP, Fässler R, Geiger B, Medalia O. The role of integrin-linked kinase in the molecular architecture of focal adhesions. J Cell Sci. 2013 Sep 15;126(Pt 18):4099-107

Li Q, Li C, Zhang YY, Chen W, Lv JL, Sun J, You QS. Silencing of integrin-linked kinase suppresses in vivo tumorigenesis of human ovarian carcinoma cells. Mol Med Rep. 2013 Mar;7(3):1050-4

Lim S, Kawamura E, Fielding AB, Maydan M, Dedhar S. Integrin-linked kinase regulates interphase and mitotic microtubule dynamics. PLoS One. 2013;8(1):e53702

Rhee SH, Han I, Lee MR, Cho HS, Oh JH, Kim HS. Role of integrin-linked kinase in osteosarcoma progression. J Orthop Res. 2013 Oct;31(10):1668-75

Watzka SB, Posch F, Pass HI, Flores RM, Hannigan GE, Bernhard D, Weber M, Mueller MR. Serum concentration of integrin-linked kinase in malignant pleural mesothelioma and after asbestos exposure. Eur J Cardiothorac Surg. 2013 May;43(5):940-5

Xie W, Zhao M, Zhou W, Guo L, Huang L, Yu W, Li X. Targeting of integrin-linked kinase with small interfering RNA inhibits VEGF-induced angiogenesis in retinal endothelial cells. Ophthalmic Res. 2013;49(3):139-49

Alique M, Civantos E, Sanchez-Lopez E, Lavoz C, Rayego-Mateos S, Rodrigues-Díez R, García-Redondo AB, Egido J, Ortiz A, Rodríguez-Puyol D, Rodríguez-Puyol M, Ruiz-Ortega M. Integrin-linked kinase plays a key role in the regulation of angiotensin II-induced renal inflammation. Clin Sci (Lond). 2014 Jul;127(1):19-31

Cano-Peñalver JL, Griera M, Serrano I, Rodríguez-Puyol D, Dedhar S, de Frutos S, Rodríguez-Puyol M. Integrin-linked kinase regulates tubular aquaporin-2 content and intracellular location: a link between the extracellular matrix and water reabsorption. FASEB J. 2014 Aug;28(8):3645-59

Nishimura M, Kumsta C, Kaushik G, Diop SB, Ding Y, Bisharat-Kernizan J, Catan H, Cammarato A, Ross RS, Engler AJ, Bodmer R, Hansen M, Ocorr K. A dual role for integrin-linked kinase and β1-integrin in modulating cardiac aging. Aging Cell. 2014 Jun;13(3):431-40

Peng H, Talebzadeh-Farrooji M, Osborne MJ, Prokop JW, McDonald PC, Karar J, Hou Z, He M, Kebebew E, Orntoft T, Herlyn M, Caton AJ, Fredericks W, Malkowicz B, Paterno CS, Carolin AS, Speicher DW, Skordalakes E, Huang Q, Dedhar S, Borden KL, Rauscher FJ 3rd. LIMD2 is a small LIM-only protein overexpressed in metastatic lesions that regulates cell motility and tumor progression by directly binding to and activating the integrin-linked kinase. Cancer Res. 2014 Mar 1;74(5):1390-403


Serrano I, McDonald P, Dedhar S. ILK (integrin-linked kinase). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5):324-332.

Gene Section Review





KITLG (KIT ligand) Alessandro Beghini, Francesca Lazzaroni

Department of Biology and Genetics, Medical Faculty, University of Milan, Italy (AB, FL)

Published in Atlas Database: August 2014

Online updated version : http://AtlasGeneticsOncology.org/Genes/MGFID142.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62120/08-2014-MGFID142.pdf DOI: 10.4267/2042/62120

This article is an update of : Larizza L, Beghini A. KITLG (KIT ligand). Atlas Genet Cytogenet Oncol Haematol 2000;4(3) Larizza L. MGF (Mast cell growth factor). Atlas Genet Cytogenet Oncol Haematol 1999;3(1)


Abstract Review on KITLG, with data on DNA/RNA, on the


Identity

Other names: MGF, SCF

HGNC (Hugo): KITLG

Location: 12q21.32

DNA/RNA

Description

KITLG/SCF is encoded by 10 exons (transcript

variant b) and 9 exons (transcript variant a).

Transcription

Transcript variant a: 5376 bp. The isoform a lacks

the primary proteolytic cleavage site. As a result,

the product encoded by this isoform is a membrane

bound protein.

Transcript variant b: 5460 bp. The transcript

isoform b contains the primary proteolytic-cleavage

site and encodes a soluble product.

Although SCF exists as a monomer, Zhang et al.

and Hsu et al. evidenced that dimerisation of SCF

has been associated with KIT receptor activation

and signal transduction. They demonstrated,

through the crystal analysis, that the SCF dimer

complex comprises of two SCF monomers with

head-to-head interaction in order to form an

elongated homo-dimer stabilised by both polar and

non polar interactions.

Alternative splicing of the SCF transcript results in

the inclusion or exclusion of an exon 6 which

contains a proteolytic cleavage site, recognised by

metalloprotease-9 enzyme that cleaves after an

alanine residue (Ala 189) in the extracellular

region, producing the 165-aminoacid soluble SCF.

There are other proteases that have been suggested

to be responsible for cleavage of membrane-bound

SCF, as chymase-1, ADAM17 and ADAM33. The

splice form that lacks the cleavage site and remains

linked to the cell surface is a result of the

alternative splicing within exon 6 which skip the

cleavage site for the metalloprotease-9.

In total, there are six alternative transcripts of SCF

in humans, out of which four encode protein

(http://www.ensembl.org).

http://www.ensembl.org/

KITLG (KIT ligand) Beghini A, Lazzaroni F


Adapted from Johan Lennartsson and Lars Rönnstrand, 2012.

Protein

Description

The membrane bound form is a surface molecule of

248 aa, that includes 23 aa of the highly

hydrophobic transmembrane domain; the second

form corresponds to a soluble protein constituted by

the first 165 aa of the extracellular domain released

by a posttranslational processing, consisting in a

proteolytic cleavage of the mature SCF in the

extracellular juxtamembrane region. The full length

transcripts encode for a transmembrane precursor of

the soluble protein; an alternative splicing that

involves the region corresponding to exon 6 of the

SCF cDNA, which contains the proteolytic

cleavage site, encodes for a surface molecule. Jiang

et al. evidenced the crystallized structure of

interaction between SCF and c-KIT and revealed

the common structure of a bundle of 4 α-helices

linked by two intra-molecular disulfide bridges.

Expression

According to description of Bedell et al., the SCF

encoding mRNA is characterized by a short 5'

untranslated region, a 0.8 kb open reading frame,

and by a long 3' untranslated region. In the 5'

region, there are three ATG motifs where the last is

used as the initiation site.

A TATA box consensus sequence (TATAAA) and

three overlapping GGCGGG motifs are located at

twenty-eight bases upstream of the transcription

initiation sites. These are binding sites for the

transcription factors TFIID and SP1, respectively.

Kobi et al. reported that the POU-homeodomain

transcription factor POU3F2, expressed in neurons

and in melanoma cells, regulates the SCF promoter

through a cluster of four closely spaced binding

sites located in the proximal promoter. It should be

noted that UVB light is also known to induce

expression of SCF in human epidermal cells both

on the mRNA level and is soluble as well as

membrane-bound SCF, but the mechanism of

induction of SCF gene expression by UVB is still

unknown.

It has been also reported that HIF-1 upregulates the

expression of SCF in response to hypoxia as well as

to growth factor receptor activation.

In Sertoli cells, SCF expression is up-regulated by

treatment with follicle stimulating hormone (FSH)

through an increasing of cAMP level.

SCF transcripts have been found in the cells

surrounding kit-positive cells, such as granulosa

and Sertoli cells, bone marrow stromal cells and in

fibroblasts, keratinocytes and mature granulocytes;

SCF expression of peripheral lymphocytes and

monocytes is still controversial.

Localisation

Plasma membrane or interstitial space.

It is interesting to note that Faber et al. showed that

disintegrin and metalloproteinase ADAM10 has an

important role in mast cell migration and

distribution.

In fact, they evidenced that ADAM 10, expressed at

high levels by mast cells, is required for SCF-

mediated mast cell migration.

Function

SCF/MGF binding of receptor KIT, with tyrosine

kinase activity, induces receptor dimerization,

autophosphorylation and signal transduction via

molecules containing SH2-domains; the soluble and

the transmembrane protein have a different

biological activity; the soluble form mainly

stimulates cellular proliferation; the membrane-

bound isoform induces an activation of the receptor

more prolonged than the soluble one.



Homology

With PDGFRb, PDGFRa, and CSF-1.

Mutations

Germinal

Human mutations are yet unknown in human

MGF/SCF gene; mouse mutations at the murine

steel (Sl) locus that encodes MGF are known and

give rise to deficiencies in pigment cells, germ

cells, and blood cells; in particular the steel-Dickie

(Sld) mouse has a 4.0-kb intragenic deletion that

truncates the Sl coding sequence; Sld mice are only

capable of encoding a soluble truncated growth

factor that lacks both transmembrane and

cytoplasmic domains.

Implicated in

Mastocytosis

Note

In skin from patients with mastocytosis, MGF was

found prevalently free in the dermis and in

extracellular spaces between keratinocytes

suggesting the presence of a soluble form of the

protein; altered distribution of mast cell growth

factor in the skin of patients with cutaneous

mastocytosis is consistent with abnormal

production of the soluble form of the factor,

resulting by an increased cleavage of SCF with

excessive release of a soluble form from the

normally membrane bound form; no sequence

abnormalities were detected in MGF mRNA.

Janson et al. evidenced that RIN3, a RAS effector,

is highly enriched in mast cells, and that is involved

in a complex with BIN2, a membrane binding

protein implicated in endocytosis. They also

demonstrated that RIN3 negatively regulates KIT

internalization process and also that KIT down-

regulation is enhanced by RIN3 activity.

Gynecological tumors

Note

Findings obtained on three cervical carcinomas

(ovarian serous adenocarcinoma, small cell

carcinoma and ovarian immature teratoma) and two

gynecological cancer cell lines (ME180 and

HGCM) demonstrate coexpression of c-Kit receptor

and SCF; these observations are consistent with the

possibility that an autocrine activation of SCF/KIT

system might be involved in gynecological

malignancies.

Small cell lung cancer

Note

SCF is expressed in small cell lung cancer (SCLC);

abundant expression of SCF and c-Kit mRNA was

seen in 32% of SCLC cell lines and 66% of SCLC

tumors; an autocrine mechanism in the

pathogenesis of SCLC is strongly suggested.

Prostate cancer

Note

Recently, Wiesner et al. suggested that SCF release

from prostate cancer (PC) cells to the extracellular

milieu has a potential contribution to prostate

cancer bone metastasis.

Pancreatic cancer

Note

c-KIT expression and SCF/c-KIT interaction are

strictly linked to invasion and proliferation of

pancreatic cancer cells. Zhang et al. recently

showed the SCF/c-KIT signaling promotes the

invasion of pancreatic cells, via HIF-1α in

normoxic condition and through PI3K/AKT and

RAS/MEK/ERK pathways.

References Martin FH, Suggs SV, Langley KE, Lu HS, Ting J, Okino KH, Morris CF, McNiece IK, Jacobsen FW, Mendiaz EA. Primary structure and functional expression of rat and human stem cell factor DNAs. Cell. 1990 Oct 5;63(1):203-11

Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock DC. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell. 1990 Oct 5;63(1):213-24

Huang EJ, Nocka KH, Buck J, Besmer P. Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. Mol Biol Cell. 1992 Mar;3(3):349-62

Ferrari S, Grande A, Manfredini R, Tagliafico E, Zucchini P, Torelli G, Torelli U. Expression of interleukins 1, 3, 6, stem cell factor and their receptors in acute leukemia blast cells and in normal peripheral lymphocytes and monocytes. Eur J Haematol. 1993 Mar;50(3):141-8

Longley BJ Jr, Morganroth GS, Tyrrell L, Ding TG, Anderson DM, Williams DE, Halaban R. Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. N Engl J Med. 1993 May 6;328(18):1302-7

Inoue M, Kyo S, Fujita M, Enomoto T, Kondoh G. Coexpression of the c-kit receptor and the stem cell factor in gynecological tumors. Cancer Res. 1994 Jun 1;54(11):3049-53

Ramenghi U, Ruggieri L, Dianzani I, Rosso C, Brizzi MF, Camaschella C, Pietsch T, Saglio G. Human peripheral blood granulocytes and myeloid leukemic cell lines express both transcripts encoding for stem cell factor. Stem Cells. 1994 Sep;12(5):521-6

Bedell MA, Brannan CI, Evans EP, Copeland NG, Jenkins NA, Donovan PJ. DNA rearrangements located over 100 kb 5' of the Steel (Sl)-coding region in Steel-panda and Steel-contrasted mice deregulate Sl expression and cause female sterility by disrupting ovarian follicle development. Genes Dev. 1995 Feb 15;9(4):455-70

Bedell MA, Copeland NG, Jenkins NA. Multiple pathways for Steel regulation suggested by genomic and sequence



analysis of the murine Steel gene. Genetics. 1996 Mar;142(3):927-34

Hsu YR, Wu GM, Mendiaz EA, Syed R, Wypych J, Toso R, Mann MB, Boone TC, Narhi LO, Lu HS, Langley KE. The majority of stem cell factor exists as monomer under physiological conditions. Implications for dimerization mediating biological activity. J Biol Chem. 1997 Mar 7;272(10):6406-15

Lemmon MA, Pinchasi D, Zhou M, Lax I, Schlessinger J. Kit receptor dimerization is driven by bivalent binding of stem cell factor. J Biol Chem. 1997 Mar 7;272(10):6311-7

Longley BJ, Tyrrell L, Ma Y, Williams DA, Halaban R, Langley K, Lu HS, Schechter NM. Chymase cleavage of stem cell factor yields a bioactive, soluble product. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9017-21

Zhang S, Anderson DF, Bradding P, Coward WR, Baddeley SM, MacLeod JD, McGill JI, Church MK, Holgate ST, Roche WR. Human mast cells express stem cell factor. J Pathol. 1998 Sep;186(1):59-66

Ashman LK. The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol. 1999 Oct;31(10):1037-51

Jiang G, Hunter T. Receptor signaling: when dimerization is not enough. Curr Biol. 1999 Jul 29-Aug 12;9(15):R568-71

Duarte RF, Frank DA. SCF and G-CSF lead to the synergistic induction of proliferation and gene expression through complementary signaling pathways. Blood. 2000 Nov 15;96(10):3422-30

Ge K, Prendergast GC. Bin2, a functionally nonredundant member of the BAR adaptor gene family. Genomics. 2000 Jul 15;67(2):210-20

Jiang X, Gurel O, Mendiaz EA, Stearns GW, Clogston CL, Lu HS, Osslund TD, Syed RS, Langley KE, Hendrickson WA. Structure of the active core of human stem cell factor and analysis of binding to its receptor kit. EMBO J. 2000 Jul 3;19(13):3192-203

Simak R, Capodieci P, Cohen DW, Fair WR, Scher H, Melamed J, Drobnjak M, Heston WD, Stix U, Steiner G, Cordon-Cardo C. Expression of c-kit and kit-ligand in benign and malignant prostatic tissues. Histol Histopathol. 2000 Apr;15(2):365-74

Zhang Z, Zhang R, Joachimiak A, Schlessinger J, Kong XP. Crystal structure of human stem cell factor: implication for stem cell factor receptor dimerization and activation. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7732-7

Kridel SJ, Chen E, Kotra LP, Howard EW, Mobashery S, Smith JW. Substrate hydrolysis by matrix metalloproteinase-9. J Biol Chem. 2001 Jun 8;276(23):20572-8

Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, Werb Z, Rafii S. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of

kit-ligand. Cell. 2002 May 31;109(5):625-37

Kajiho H, Saito K, Tsujita K, Kontani K, Araki Y, Kurosu H, Katada T. RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway. J Cell Sci. 2003 Oct 15;116(Pt 20):4159-68

Baba H, Uchiwa H, Watanabe S. UVB irradiation increases the release of SCF from human epidermal cells. J Invest Dermatol. 2005 May;124(5):1075-7

Reber L, Da Silva CA, Frossard N. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur J Pharmacol. 2006 Mar 8;533(1-3):327-40

Fischer B, Marinov M, Arcaro A. Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): what have we learned so far? Cancer Treat Rev. 2007 Jun;33(4):391-406

Han ZB, Ren H, Zhao H, Chi Y, Chen K, Zhou B, Liu YJ, Zhang L, Xu B, Liu B, Yang R, Han ZC. Hypoxia-inducible factor (HIF)-1 alpha directly enhances the transcriptional activity of stem cell factor (SCF) in response to hypoxia and epidermal growth factor (EGF). Carcinogenesis. 2008 Oct;29(10):1853-61

Pedersen M, Löfstedt T, Sun J, Holmquist-Mengelbier L, Påhlman S, Rönnstrand L. Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells. Biochem Biophys Res Commun. 2008 Dec 5;377(1):98-103

Wiesner C, Nabha SM, Dos Santos EB, Yamamoto H, Meng H, Melchior SW, Bittinger F, Thüroff JW, Vessella RL, Cher ML, Bonfil RD. C-kit and its ligand stem cell factor: potential contribution to prostate cancer bone metastasis. Neoplasia. 2008 Sep;10(9):996-1003

Kobi D, Steunou AL, Dembélé D, Legras S, Larue L, Nieto L, Davidson I. Genome-wide analysis of POU3F2/BRN2 promoter occupancy in human melanoma cells reveals Kitl as a novel regulated target gene. Pigment Cell Melanoma Res. 2010 Jun;23(3):404-18

Zhang M, Ma Q, Hu H, Zhang D, Li J, Ma G, Bhat K, Wu E. Stem cell factor/c-kit signaling enhances invasion of pancreatic cancer cells via HIF-1α under normoxic condition. Cancer Lett. 2011 Apr 28;303(2):108-17

Janson C, Kasahara N, Prendergast GC, Colicelli J. RIN3 is a negative regulator of mast cell responses to SCF. PLoS One. 2012;7(11):e49615

Lennartsson J, Rönnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev. 2012 Oct;92(4):1619-49

Faber TW, Pullen NA, Fernando JF, Kolawole EM, McLeod JJ, Taruselli M, Williams KL, Rivera KO, Barnstein BO, Conrad DH, Ryan JJ. ADAM10 is required for SCF-induced mast cell migration. Cell Immunol. 2014 Jul;290(1):80-8


Beghini A, Lazzaroni F. KITLG (KIT ligand). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5):333-336.

Gene Section Short Communication





ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase) Samuel J Klempner, Sai-Hong Ou

University of California Irvine Medical Center, Orange, CA. [email protected]; [email protected]

Published in Atlas Database: January 2014

Online updated version : http://AtlasGeneticsOncology.org/Genes/ROS1ID42144ch6q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62121/01-2014-ROS1ID42144ch6q22.pdf DOI: 10.4267/2042/62121


Abstract

ROS1 is proto-oncogene encoding a type I integral

membrane protein with receptor tyrosine kinase

(RTK) activity.

ROS1 is a member of the insulin receptor family

and is involved in downstream signalling processes

involved in cell growth and differentiation.

Keywords

ROS1; tyrosine kinase; insulin receptor family; cell

growth and differentiation; cancer

Identity

Other names: c-ros-1, MCF3, ROS

HGNC (Hugo): ROS1

Location: 6q22.1

Note

ROS1 is proto-oncogene encoding a type I integral

membrane protein with receptor tyrosine kinase

(RTK) activity.

ROS1 is a member of the insulin receptor family

and is involved in downstream signalling processes

involved in cell growth and differentiation.

DNA/RNA

Description

The ROS1 gene is highly conserved from

drosophila through zebrafish, rat, cow, rhesus, and

homo sapiens. Refseq NM_002944.

Protein

Description

ROS1 gene encodes a 2,347 amino acid protein

with a molecular weight of 263,915 Daltons (NCBI:

P08922). This protein is a type I single pass

integral membrane protein with tyrosine kinase

activity. SwissProt identifier P08922, Protein

NP_002935

Expression

ROS1 expression is involved in regionalization of

the proximal epididymal epithelium. Expression

levels have been highest in liver, platelelts, T-cells

and monocytes, but is found across nearly all cell

types.

Localisation

ROS1 is localized to the cell plasma membrane and

contains both extracellular and intracellular

domains.

Function

ROS1 functions as an orphan receptor tyrosine

kinase with an unestablished ligand. ROS1 directly

interacts via an SH2 1 domain with PTPN6 which

drives ROS1 dephosphorylation (Charest et al.,

2006). ROS1 has also been suggested to interact

with PTPN11 leading to PI3K/mTOR signaling,

and to mediate phosphorylation of VAV3 (Charest

et al., 2006). The ligand for wild type ROS1 is

unknown and the normal function remains unclear

despite the above associations.

ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase) Klempner SJ, Ou SH


Homology

ROS1 shares significant homology with other

members of the insulin growth factor receptor

family, and the gene is highly conserved back

through drosophila melanogaster.

Mutations

Germinal

None established.

Somatic

The intrachromosomal del(6)(q21q22) deletion has

been identified in glioblastoma multiforme and

leads to the formation of a constitutive active

GOPC-ROS1 protein (Charest et al., 2003). In non-

small cell lung cancer (NSCLC) the SLC34A2-

ROS1 chimeric protein also holds kinase activity.

A CD74-ROS1 chimeric protein has also been

identified in NSCLC (Awad et al., 2013).

Implicated in

Non-small cell lung cancer, renal oncocytoma, gastric cancer, glioblastoma multiforme, cholangiocarcinoma colorectal cancer.

Note

There has been a rapidly expanding appreciation of

ROS1 fusion proteins in the tumorigenesis of

multiple malignancies as discussed below (Charest

et. al., 2003, Gu et al., 2011, Rimkunas et al., 2012,

Takeuchi et al.,2012, Awad et al., 2013, Lee et al.,

2013).

Disease

ROS1 rearrangements occur in <2% of NSCLC and

are enriched for in adenocarcinoma and young

never smokers (Bergethon et al., 2012).

Prognosis

To date ROS1 has not been clearly implicated as an

independent prognostic variable. ROS1

rearrangements may predict sensitivity to the ALK-

inhibitor Crizotinib in NSCLC. Small molecule

inhibitor screens have also identified foretinib as a

potent inhibitor of multiple ROS1 fusion proteins.

Additionaly, ROS1 mutation has been observed as a

acquired resistance mechanism to crizotinib.

Davare and colleagues have shown that foretinib is

capable of inhibiting the G2032R ROS1 mutant

which is resistant to crizotinib (Davare et al., 2013).

Cytogenetics

ROS1 rearrangements have been documented with

the following fusion partners; CCDC6, CD74,

CEP85L, also called C6orf204, CLTC, EZR,

GOPC, KDELR2, LRIG3, SDC4, SLC34A2, and

TPM3.

Translocations and fusion proteins: t(1;6)(q21;q22)

TPM3/ROS1; t(4;6)(p15;q22) SLC34A2/ROS1;

t(5;6)(q33;q22) CD74/ROS1; t(6;6)(q22;q22)

GOPC/ROS1; t(6;6)(q22;q22) CEP85L/ROS1;

t(6;6)(q22;q25) EZR/ROS1; t(6;7)(q22;p22)

KDELR2/ROS1; t(6;10)(q22;q21) CCDC6/ROS1;

t(6;12)(q22;q14) LRIG3/ROS1;

t(6;17)(q22;q23)CLTC/ROS1; t(6;20)(q22;q12)

SDC4/ROS1 (Charest et. Al., 2003, Gu et al., 2011,

Rimkunas et al., 2012, Takeuchi et al., 2012, Awad

et al., 2013, Lee et al., 2013, Mitelman et al., 2015).

Within NSCLC ROS1 rearrangements are non-

overlapping with EGFR, KRAS, and ALK genomic

ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase) Klempner SJ, Ou SH


alterations (Davies et al., 2012, Awad et al., 2013,

Go et al., 2013).

Breakpoints

Note

Within the COSMIC database ROS1 chromosomal

rearrangements have been documented with the

following fusion partners ; CD74, EZR, GOPC,

SDC4, TPM3, SLC34A2, and LRIG3 (COSMIC,

accessed 12/2013).

References Mitelman F Johansson B and Mertens F. Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer http://cgap.nci.nih.gov/Chromosomes/Mitelman

Awad MM, Katayama R, McTigue M, Liu W, Deng YL, Brooun A, Friboulet L, Huang D, Falk MD, Timofeevski S, Wilner KD, Lockerman EL, Khan TM, Mahmood S, Gainor JF, Digumarthy SR, Stone JR, Mino-Kenudson M, Christensen JG, Iafrate AJ, Engelman JA, Shaw AT. Acquired resistance to crizotinib from a mutation in CD74-ROS1 N Engl J Med 2013 Jun 20;368(25):2395-401

Aisner DL, Nguyen TT, Paskulin DD, Le AT, Haney J, Schulte N, Chionh F, Hardingham J, Mariadason J, Tebbutt N, Doebele RC, Weickhardt AJ, Varella-Garcia M. ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers Mol Cancer Res 2014 Jan;12(1):111-8

Charest A, Lane K, McMahon K, Park J, Preisinger E, Conroy H, Housman D. Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21) Genes Chromosomes Cancer 2003 May;37(1):58-71

Charest A, Wilker EW, McLaughlin ME, Lane K, Gowda R, Coven S, McMahon K, Kovach S, Feng Y, Yaffe MB, Jacks T, Housman D. ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice Cancer Res 2006 Aug 1;66(15):7473-81

Gu TL, Deng X, Huang F, Tucker M, Crosby K, Rimkunas V, Wang Y, Deng G, Zhu L, Tan Z, Hu Y, Wu C, Nardone J, MacNeill J, Ren J, Reeves C, Innocenti G, Norris B, Yuan J, Yu J, Haack H, Shen B, Peng C, Li H, Zhou X, Liu X, Rush J, Comb MJ. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma PLoS One 2011 Jan 6;6(1):e15640

Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ. ROS1 rearrangements define a unique molecular class of lung cancers J Clin Oncol 2012 Mar 10;30(8):863-70

Chin LP, Soo RA, Soong R, Ou SH. Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer J Thorac Oncol 2012

Nov;7(11):1625-30

Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, Berge EM, Terracciano LM, Cappuzzo F, Incarbone M, Roncalli M, Alloisio M, Santoro A, Camidge DR, Varella-Garcia M, Doebele RC. Identifying and targeting ROS1 gene fusions in non-small cell lung cancer Clin Cancer Res 2012 Sep 1;18(17):4570-9

Ou SH, Tan J, Yen Y, Soo RA. ROS1 as a 'druggable' receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway Expert Rev Anticancer Ther 2012 Apr;12(4):447-56

Rimkunas VM, Crosby KE, Li D, Hu Y, Kelly ME, Gu TL, Mack JS, Silver MR, Zhou X, Haack H. Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion Clin Cancer Res 2012 Aug 15;18(16):4449-57

Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y. RET, ROS1 and ALK fusions in lung cancer Nat Med 2012 Feb 12;18(3):378-81

Yasuda H, de Figueiredo-Pontes LL, Kobayashi S, Costa DB. Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer J Thorac Oncol 2012 Jul;7(7):1086-90

Cilloni D, Carturan S, Bracco E, Campia V, Rosso V, Torti D, Calabrese C, Gaidano V, Niparuck P, Favole A, Signorino E, Iacobucci I, Morano A, De Luca L, Musto P, Frassoni F, Saglio G. Aberrant activation of ROS1 represents a new molecular defect in chronic myelomonocytic leukemia Leuk Res 2013 May;37(5):520-30

Davare MA, Saborowski A, Eide CA, Tognon C, Smith RL, Elferich J, Agarwal A, Tyner JW, Shinde UP, Lowe SW, Druker BJ. Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins Proc Natl Acad Sci U S A 2013 Nov 26;110(48):19519-24

Davies KD, Doebele RC. Molecular pathways: ROS1 fusion proteins in cancer Clin Cancer Res 2013 Aug 1;19(15):4040-5

Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions Oncologist 2013;18(7):865-75

Go H, Kim DW, Kim D, Keam B, Kim TM, Lee SH, Heo DS, Bang YJ, Chung DH. Clinicopathologic analysis of ROS1-rearranged non-small-cell lung cancer and proposal of a diagnostic algorithm J Thorac Oncol 2013 Nov;8(11):1445-50

Lee J, Lee SE, Kang SY, Do IG, Lee S, Ha SY, Cho J, Kang WK, Jang J, Ou SH, Kim KM. Identification of ROS1 rearrangement in gastric adenocarcinoma Cancer 2013 May 1;119(9):1627-35

Ou S, Bang Y, Camidge D, et al.. Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2013;31:8032


Klempner SJ, Ou SH. ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5):337-339.

Gene Section Review





MICA (MHC class I polypeptide-related sequence A) Zain Ahmed, Medhat Askar

Cleveland Clinic/, Cleveland, OH; [email protected]

Published in Atlas Database: July 2014

Online updated version : http://AtlasGeneticsOncology.org/Genes/MICAID41364ch6p21.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62122/07-2014-MICAID41364ch6p21.pdf DOI: 10.4267/2042/62122


Abstract

Human Major Histocompatibility Complex (MHC)

Class I Chain-Related gene A (MICA) is located 46

Kb centromeric to the HLA-B locus on the short

arm of human chromosome 6 and encodes for a 62-

kda cell surface glycoprotein. It is expressed on

endothelial cells, dendritic cells, fibroblasts,

epithelial cells, and many tumours and serves as

target for both cellular and humoral immune

responses in transformed cells. MICA protein at

normal states has a low level of expression in

epithelial tissues but is upregulated in response to

various stimuli of cellular stress. MICA also

functions as a ligand recognized by the activating

receptor NKG2D that is expressed on the surface of

NK, NKT, CD8+ and TCRγδ+ T cells. Allelic

variants of MICA due to a single amino acid

substitution at position 129 in the α2 domain have

been reported to result in large differences in

NKG2D binding. These variable affinities have

been suggested to affect thresholds of NK cell

triggering and T cell modulation in autoimmune

diseases and malignancies.

MICA molecules exist also in soluble forms

(sMICA) and altered serum levels of sMICA have

been reported in multiple states of health and

disease.

Keywords

MICA, MHC, Malignancy, Autoimmunity, NK

cells; Transplantation; Rejection; GVHD

Identity

Other names

MHC (Human Major Histocompatibility Complex)

Class I Chain-Related Gene A,

MHC Class I Chain-related Protein A,

MHC class I-related chain A,

MIC-A,

PERB11.1

HGNC (Hugo): MICA

Location: 6p21.33

Figure 1: Chromosomal location of MICA genes shown on a map of the MHC on chromosome 6p21.3 (not to scale). Chromosome 6 [Drawing modified from the National Library of Medicine, the National Center for Biotechnology Information

public website (2013)]

MICA (MHC class I polypeptide-related sequence A) Ahmed Z, Askar M


Figure 2: The MICA gene spans a 11,720-bp stretch of DNA was located 46,445 bp centromeric of the HLA-B locus on the short

arm of human chromosome 6 (Mizuki et al., 1997).

DNA/RNA

Description

The MICA gene was described in 1994 among a

group of genes within the MHC class I region

(Bahram et al., 1994). It is a member of the MIC

gene family, which consists of 7 members (MICA-

MICG). MICA is classified as a non-classical MHC

class I gene as opposed to classical MHC class I

genes encoding the commonly known Human

Leukocyte Antigen (HLA) proteins. Similar to the

HLA genes, the MICA gene is highly polymorphic.

One hundred alleles have been reported (according

to IMGT Release 3.17.0, 2014-07-14), with new

alleles being continuously described and added to

the database. As such it is significantly less

polymorphic than HLA loci A (2,884 alleles), B

(3,589), C (2,375), DRB1 (1,540), DQB1 (664),

and DPB1 (422). However, MICA is more

polymorphic than HLA loci G (50), DRB3 (58),

DRB4 (15), DRB5 (20), DRA (7), DQA1 (52),

DPA1 (38), and its closely related MICB gene (40)

(Robinson et al., 2013).

MICA gene is organized into 7 exons of which

exon 5 encodes the transmembrane (TM) region of

the MICA molecule. TM encodes the repeat

polymorphism (GCT/Ala) and eight types of

repeats have been described as A4, A5, A5.1, A6,

A7, A8, A9, and A10 (Gambelunghe et al., 2006;

Zou et al., 2006). The combinations of extracellular

and TM types facilitates the identification of the

MICA alleles and reduces the number of potential

ambiguous typings in heterozygous individuals.

This combination identifies MICA alleles based on

polymorphisms in the TM region as well as

elsewhere, e.g., MICA*007:01/A4,

MICA*008:01/A5.1, etc.

Transcription

MICA gene encodes 383 amino acids polypeptide.

MICA is up-regulated on human endothelial cells

by the pro-inflammatory cytokine TNFα. This up-

regulation is controlled at the transcriptional level

by a master regulatory control element positioned

130-base pair (bp) upstream of the MICA

transcription start site integrating input from the

NF-kB and heat shock pathways (Lin et al., 2012).

Pseudogene

Of the MIC gene family, only MICA and MICB are

true genes with protein products while the

remaining (MICC-MICG) are pseudogenes.

Protein

Note

Due to synonymous substitutions being the only

differences among some of the MICA alleles, the

100 MICA alleles encode for only 79 distinct

proteins. Two of the MICA alleles are null alleles

with no expressed protein products. MICA

molecules are considered non-classical MHC class I

molecules rather than human leukocyte antigens

(HLA) since they are not expressed on the surface

of human leukocytes. Nevertheless they are

expressed on endothelial cells, dendritic cells,

fibroblasts, epithelial cells, and many tumors and



Figure 3: Diagram of comparison among HLA-Class I, MICA and sMICA molecules

serve as targets for both cellular and humoral

immune responses (Bahram et al., 1994; Zou and

Stastny, 2010). MICA protein at normal states has a

low level of expression in epithelial tissues but is

upregulated in many tumors and under various

stimuli of cellular stress including heat shock

proteins (Groh et al., 1996). Similar to MHC class

I, MICA molecules have 3 extracellular

immunoglobulin-like domains, a transmembrane

domain and intracellular cytoplasmic tail. However,

unlike class I, MICA is not covalently bound a

monomorphic β2 microglobulin and its peptide

binding groove is empty and does not present

peptides (Figure 3).

Allelic variants of MICA based on a single amino

acid substitution at position 129 in the α2 domain

have been reported to result in large differences in

the affinity of binding to the activating natural killer

group 2, member D (NKG2D) (Steinle et al., 2001).

MICA alleles with a methionine (M) or valine (V)

have been classified as having strong or weak

binding affinity for NKG2D, respectively. These

variable affinities have been suggested to affect

thresholds of NK cell triggering and T cell

modulation and consequently influencing clinical

phenotypes in autoimmune disorders and

malignancies (Amroun et al., 2005; Douik et al.,

2009).

MICA molecules exist also in soluble forms

(sMICA) encompassing three extracellular domains

(Salih et al., 2002). ADAM, a disintegrin and

metalloproteinase, is reported to mediate sMICA

generation by cleavage of the molecule in the α3

domain close to the papain cleavage site (Figure X),

however the precise location of the cleavage site is

still unknown (Waldhauer et al., 2008). sMICA are

not normally detected in sera of healthy donors and

tumor cells are the major source of sMICA

generation (Holdenrieder et al., 2006). In addition

to patients with malignancies, sMICA is detected in

the sera of patients with autoimmune diseases,

acute bacterial infections, renal insufficiency, and

cholestasis (Holdenrieder et al., 2007). Unlike the

surface-bound form of MICA that stimulates

immune responses, the secreted soluble counterpart,

sMICA abates immune responses primarily by

down regulating NKG2D expression which impairs

the cellular cytotoxicity of T cells and NK cells

against tumor cells (Groh et al., 2002). This may

partly explain why higher levels of sMICA were

observed in the serum of chronically infected

individuals compared to healthy controls and HIV-1

controllers (Nolting et al., 2010). Similarly CMV

infection triggers shedding of sMICA (Andresen et

al., 2009).

Description

383 amino acids in length (including the 23 amino

acids leader sequence that is lost from the 360

amino acid mature protein), 42,915 Da protein,

undergoes N-glycoslation as post-translational

modification, although not required to interact with

NKG2D. MICA has three external (α1, α2, α3), a

transmembrane and an intracytoplasmic domains

(figure 4).

Expression

Co-dominantly and constitutively expressed on cell

membranes of human epithelial, endothelial,

fibroblasts cells, keratinocytes, monocytes,

dendritic cells, thymic medulla, and gastrointestinal

epithelial cells but not on the surface of other

healthy cells (Zwirner et al., 1999). Activated

CD4+ and CD8+ T cells are shown to express

MICA. Nuclear factor (NF)-kB regulates MICA

expression on activated T lymphocytes by binding

to a specific sequence in the long intron 1 of the

MICA gene (Molinero et al., 2004). MICA

expression is also up-regulated on stressed cells,

tumour cells, and pathogen-infected cells (Mistry

and O'Callaghan, 2007). It's noteworthy that in vitro

CMV infection strongly induces expression of

MICA (Groh et al., 2001). Similarly, respiratory

syncytial virus (RSV) infection of epithelial cells



Figure 4: The amino acid sequence of the full length MICA molecule. Source: IMGT/HLA online database (Robinson et al., 2013)

up-regulated cell surface expression of MICA and

levels of soluble MICA (Zdrenghea et al., 2012).

It is also reported that CMV induced expression on

the surface of fibroblasts is skewed towards a

common form of MICA (A5.1), which has a

nucleotide insertion in exon 5 corresponding to the

transmembrane region and no cytoplasmic tail and

less activation of the NKG2D pathway (Zou et al.,

2005).

Localisation

Cell surface as a single-pass type 1 membrane

protein

Function

Like other MHC Class I molecules, MICA is a

highly polymorphic MHC Class I molecule

expressed on the cell surface of cells mentioned

above.

However, unlike other classical MHC Class I

molecules, MICA is not involved in antigen

presentation because its peptide-binding groove is

too narrow to present antigens and is not associated

with β2-microglobulin (Groh et al., 1996).

MICA is expressed under cellular stress and is a

ligand for NKG2D receptor expressed on surface of

NK, NKT, CD8+ and TCRγδ T cells (Bauer et al.,

1999). NKG2D binding results in up-regulation of

MICA and ultimately cytotoxicity and release of

IFN? by NKG2D-expressing cells.

Homology

Searching the non-redundant protein sequences (nr)

database for the protein sequences similar to the

MICA reference amino acid sequence (MICA*001)

using Blastp (protein-protein BLAST) tool publicly

available from the website of The National Center

for Biotechnology Information

(https://blast.ncbi.nlm.nih.gov/Blast) showed that

the closest protein sequences are MICB followed

by MHC class I (Wheeler and Bhagwat, 2007). The

phylogenetic distance among these 3 sequences as

determined by the online ClustalW2 (version

CLUSTAL 2.1) Multiple Sequence Alignments tool

publicly available at the website of the European

Bioinformatics Institute of the European Molecular

Biology Laboratory (EMBL-EBI)

(http://www.ebi.ac.uk/Tools/msa/clustalw2/) is

shown in figure (5) (McWilliam et al., 2013).

Aligning MICA *001 and MICB reference amino

acid sequence (MICB *001) using the same

ClustalW2 tool yields scores of 83.03% sequence

identity (Figure 6). Similarly alignment of

MICA*001 and HLA class I consensus amino acid

sequence yielded an identity score of 26.47%

between (Figure 7).

Figure 5: A phylogram of the genetic distance between HLA class I consensus sequence, MICA and MICB reference alleles. This Phylogram considers only amino acid sequence of the 'Mature Protein' excluding the 23 amino acids leader sequence in MICA

and MICB reference sequences and 24 amino acids leader sequence in the Class I consensus sequence due to lack of consensus among leader sequences of loci HLA-A, B, and C



Figure 6: Sequence alignment between MICA (MICA*001) and MICB (MICB*001) reference sequences. This alignment considers the 'Full Length Protein' including the 23 amino acids leader sequence that is lost in the mature protein

Figure 7: Sequence alignment between MICA reference sequence (MICA*001) and HLA Class I consensus sequence. This alignment considers only the 'Mature Protein' excluding the 23 amino acids leader sequence in MICA reference sequence and 24 amino acids leader sequence in the Class I consensus sequence due to lack of consensus among leader sequences of loci HLA-

A, B, and C



Mutations

Note

Similar to HLA genes, each allelic variant of MICA

is given a distinct name that is officiated by the

WHO Nomenclature Committee for Factors of the

HLA System. The following are the 100 recognized

MICA alleles (according to IMGT Release 3.17.0,

2014-07-14): MICA*001, MICA*002:01,

MICA*002:02, MICA*002:03, MICA*002:04,

MICA*004, MICA*005, MICA*006,

MICA*007:01, MICA*007:02, MICA*007:03,

MICA*007:04, MICA*007:05, MICA*007:06,

MICA*008:01:01, MICA*008:01:02,

MICA*008:02, MICA*008:03, MICA*008:04,

MICA*008:05, MICA*009:01, MICA*009:02,

MICA*010:01, MICA*010:02, MICA*011,

MICA*012:01, MICA*012:02, MICA*012:03,

MICA*012:04, MICA*013, MICA*014,

MICA*015, MICA*016, MICA*017,

MICA*018:01, MICA*018:02, MICA*019,

MICA*020, MICA*022, MICA*023, MICA*024,










MICA*061, MICA*062, MICA*063N,

MICA*064N, MICA*065, MICA*066,





MICA*084 (Robinson et al., 2013).

Implicated in

Pregnancy

Note

MICA genotypes MICA5.0/5.1 were associated

with autoimmune type 1 diabetes with onset during

pregnancy (Torn et al., 2004).

On the other hand sMIC molecules released from

the placenta is considered as a possible immune

escape mechanism important for fetal survival

(Mincheva-Nilsson et al., 2006).

sMIC was also reported as a novel blood biomarker

of the chances of a viable baby in infertile women

undergoing in vitro fertilization (Porcu-Buisson et

al., 2007).

Consistent with these reports is the finding of

reduced production of sMICA by the aged placenta

playing a role in parturition (Huang et al., 2011).

Malignancies

Note

MICA 129 M/V dimorphism with variable NKG2D

binding affinities has been reported to affect

thresholds of NK cell triggering and T cell

modulation in malignancies (Douik et al., 2009). In

cancer patients, elevated sMICA levels are

significantly correlated with cancer stage,

differentiation, and metastasis (Holdenrieder et al.,

2006). MICA is also expressed in abundance in

large granular lymphocyte leukemia cells.

Neutrophil counts were inversely correlated with

MICA expression and MICA*00801/A5.1 was

reported in higher frequency in patients with large

granular lymphocyte leukemia (Viny et al., 2010).

Graft versus host disease (GVHD)

Disease

GVHD is an immunological disorder that affects

many organ systems, including the gastrointestinal

tract, liver, skin, and lungs and results from donor-

host disparities in major and minor

histocompatibility antigens following solid organs

and hematopoietic stem cell transplantation (Ferrara

et al., 2009; Sharma et al., 2012).

Prognosis

GVHD remains a significant hurdle in overcoming

the morbidity and mortality associated with

hematopoietic stem cell transplantation (Dhir et al.,

2014).

Because of its genomic location between MHC

Class I and Class II genes, there is strong linkage

disequilibrium between many MICA and HLA-B

alleles. MICA could also serve as a genetic marker

of recombination between MHC classes I and II in

otherwise MHC matched individuals where MICA

mismatched individuals would be predicted to have

mismatched haplotypes whereas the MICA

matched pairs may or may not be haplotype

matched. This distinction is biologically relevant

since MHC haplotype mismatching in otherwise

HLA matched donor/recipient pairs was reported in

association with a statistically significantly

increased risk of severe acute GvHD (Petersdorf et

al., 2007). Donor/recipient MICA mismatches were

associated with increased risk of severe acute

GVHD and were also reported to have a synergistic

effect with HLA-DPB1 mismatches on the risk of

severe acute GVHD (Askar et al., 2012). MICA-

129 genotype, sMICA, and anti-MICA antibodies

were reported as biomarkers of chronic GVHD

(Boukouaci et al., 2009).

Allograft rejection

Disease

MICA mismatch is associated with presence of

MICA antibodies in serum of solid organ transplant



recipient, which in turn is associated with acute

rejection. Anti-MICA sera can bind to endothelial

cells from MICA A5.1 donors. Thus, MICA A5.1

can potentially serve as an alloantigen and possibly

mediate an alloimmune response. Transplant

recipients can also develop donor-specific

antibodies to MICA. MICA DSA were associated

with decreased graft function.

Prognosis

Presensitization of kidney-transplant recipients to

MICA antigens was reported in association with an

increased frequency of graft loss and was suggested

to contribute to allograft loss among recipients who

are otherwise well matched for HLA (Zou et al.,

2007).

Donor MICA A5.1 mismatch is associated with

anti-MICA antibody formation and increased

proteinuria in kidney recipients. MICA*001,*004,

*007, *009, *012, and *018 are more prevalent in

patients with impaired renal function than normal

function.

Psoriasis

Disease

Psoriasis is a disease of the skin characterized by

chronic inflammation leading to scaly plaques.

Prognosis

MICA transmembrane (MICA-TM) A9 allele is

associated with increased susceptibility to psoriasis

in Asian populations (Song et al., 2014).

Psoriatic arthritis

Disease

Psoriastic arthritis is a seronegative inflammatory

arthritis that develops in a more than 10% of

patients with psoriasis. Like other seronegative

spondyloarthropathies, psoriastic arthritis is

associated with HLA-B27 allele.

Prognosis

Psoriastic arthritis tends not to be as serve as

rheumatoid arthritis in joint destruction.

MICA-TM A9 allele is associated with a PsA

susceptibility in European populations (Amroun H

et. al, 2005).

Since MICA is located 46 kb centromeric to the

HLA-B gene cluster, its location may explain its

association.

Ankylosing spondylitis (AS)

Disease

Ankylosing spondylitis is a seronegative

spondyloarthropathies associated with HLA-B27

allele. AS is characterized by chronic inflammation

of joints typically in the axial skeleton, such as

spine and sacroiliac joints, leading to destruction of

cartilage and ultimately bony ankylosis causing

severe joint immobility. AS is also characterized by

extraarticular manifestations including uveitis,

aortitis, and amyloidosis.

Prognosis

MICA alleles are associated with AS in both HLA-

B27-positive and B27-negative AS patients. The

MICA*007:01 allele is associated with increased

susceptibility to AS in Caucasian and Han Chinese

populations. The MICA*019 allele increases the

risk for AS in Chinese patients. In a small cohort

study of of Algerian patients with AS, MICA-129

allele was associated with an early onset of AS

(Tong, 2013).

Systemic lupus erythematosus (SLE)

Prognosis

Poor (Susceptibility)

Polymorphisms of MICA TM region have been

reported in association with susceptibility to SLE

(Yoshida et al., 2011).

Hepatitis B and C

Note

There is an association of MICA rs2596542G/A

promoter variant and substitutions MICA-

129Met/Val, MICA-251Gln/Arg, MICA-

175Gly/Ser with HBV-induced hepatocellular

carcinoma and HBV persistence (Kumar V, 2012).

Disease

Hepatitis B and C are viral infections that can

chronically predispose to hepatocellular carcinoma.

MICA genetic variations and soluble MICA levels

may serve as predictive biomarker for HBV- and

HCV-induced HCC. Expression of MICA may be

induced by the stress of viral infection and play a

role in tumor immune surveillance (Kumar V,

2012).

Prognosis

Poor. HBV-induced HCC patients with the high

serum level of sMICA have shown to have worse

prognosis than those with low serum level of

sMICA (?5 pg/ml).

A single nucleotide polymorphism of MICA

rs2596542 located in MICA promotor region is

associated with hepatitis C-induced HCC in a

Japanese patients and serum levels of soluble

MICA (sMICA).

References Bahram S, Bresnahan M, Geraghty DE, Spies T. A second lineage of mammalian major histocompatibility complex class I genes Proc Natl Acad Sci U S A 1994 Jul 5;91(14):6259-63

Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium Proc Natl Acad Sci U S A 1996 Oct 29;93(22):12445-50

Mizuki N, Ando H, Kimura M, Ohno S, Miyata S, Yamazaki



M, Tashiro H, Watanabe K, Ono A, Taguchi S, Sugawara C, Fukuzumi Y, Okumura K, Goto K, Ishihara M, Nakamura S, Yonemoto J, Kikuti YY, Shiina T, Chen L, Ando A, Ikemura T, Inoko H. Nucleotide sequence analysis of the HLA class I region spanning the 237-kb segment around the HLA-B and -C genes Genomics 1997 May 15;42(1):55-66

Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA Science 1999 Jul 30;285(5428):727-9

Zwirner NW, Dole K, Stastny P. Differential surface expression of MICA by endothelial cells, fibroblasts, keratinocytes, and monocytes Hum Immunol 1999 Apr;60(4):323-30

Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells Nat Immunol 2001 Mar;2(3):255-60

Steinle A, Li P, Morris DL, Groh V, Lanier LL, Strong RK, Spies T. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family Immunogenetics 2001 May-Jun;53(4):279-87

Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation Nature 2002 Oct 17;419(6908):734-8

Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding J Immunol 2002 Oct 15;169(8):4098-102

Molinero LL, Fuertes MB, Girart MV, Fainboim L, Rabinovich GA, Costas MA, Zwirner NW. NF-kappa B regulates expression of the MHC class I-related chain A gene in activated T lymphocytes J Immunol 2004 Nov 1;173(9):5583-90

Törn C, Gupta M, Sanjeevi CB, Aberg A, Frid A, Landin-Olsson M. Different HLA-DR-DQ and MHC class I chain-related gene A (MICA) genotypes in autoimmune and nonautoimmune gestational diabetes in a Swedish population Hum Immunol 2004 Dec;65(12):1443-50

Amroun H, Djoudi H, Busson M, Allat R, El Sherbini SM, Sloma I, Ramasawmy R, Brun M, Dulphy N, Krishnamoorthy R, Toubert A, Charron D, Abbadi MC, Tamouza R. Early-onset ankylosing spondylitis is associated with a functional MICA polymorphism. Hum Immunol. 2005 Oct;66(10):1057-61

Zou Y, Bresnahan W, Taylor RT, Stastny P. Effect of human cytomegalovirus on expression of MHC class I-related chains A J Immunol 2005 Mar 1;174(5):3098-104

Gambelunghe G, Brozzetti AL, Ghaderi M, Tortoioli C, Falorni A. MICA A8: a new allele within MHC class I chain-related A transmembrane region with eight GCT repeats Hum Immunol 2006 Dec;67(12):1005-7

Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A, Salih HR. Soluble MICA in malignant diseases Int J Cancer 2006 Feb 1;118(3):684-7

Mincheva-Nilsson L, Nagaeva O, Chen T, Stendahl U, Antsiferova J, Mogren I, Hernestål J, Baranov V. Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: a possible novel immune escape mechanism for fetal survival J Immunol 2006 Mar 15;176(6):3585-92

Zou Y, Han M, Wang Z, Stastny P. MICA allele-level typing by sequence-based typing with computerized assignment

of polymorphic sites and short tandem repeats within the transmembrane region Hum Immunol 2006 Mar;67(3):145-51

Mistry AR, O'Callaghan CA. Regulation of ligands for the activating receptor NKG2D Immunology 2007 Aug;121(4):439-47

Petersdorf EW, Malkki M, Gooley TA, Martin PJ, Guo Z. MHC haplotype matching for unrelated hematopoietic cell transplantation PLoS Med 2007 Jan;4(1):e8

Porcu-Buisson G, Lambert M, Lyonnet L, Loundou A, Gamerre M, Camoin-Jau L, Dignat-George F, Caillat-Zucman S, Paul P. Soluble MHC Class I chain-related molecule serum levels are predictive markers of implantation failure and successful term pregnancies following IVF Hum Reprod 2007 Aug;22(8):2261-6

Wheeler D, Bhagwat M. BLAST QuickStart: example-driven web-based BLAST tutorial Methods Mol Biol 2007;395:149-76

Zou Y, Stastny P, Süsal C, Döhler B, Opelz G. Antibodies against MICA antigens and kidney-transplant rejection N Engl J Med 2007 Sep 27;357(13):1293-300

Waldhauer I, Goehlsdorf D, Gieseke F, Weinschenk T, Wittenbrink M, Ludwig A, Stevanovic S, Rammensee HG, Steinle A. Tumor-associated MICA is shed by ADAM proteases Cancer Res 2008 Aug 1;68(15):6368-76

Andresen L, Hansen KA, Jensen H, Pedersen SF, Stougaard P, Hansen HR, Jurlander J, Skov S. Propionic acid secreted from propionibacteria induces NKG2D ligand expression on human-activated T lymphocytes and cancer cells. J Immunol. 2009 Jul 15;183(2):897-906

Askar, M., Rybicki, L., Zhang, A., Thomas, D., Kalaycio, M., Copelan, E., Pohlman, B., Dean, R., Duong, H., Hanna, R., et al.. The Impact of The Major Histocompatibility Complex Class I-Related Chain A (MICA) and Human Leukocyte Antigen (HLA)-DP Mismatches On Severe Acute GVHD in Patients Receiving Allogeneic Hematopoietic Progenitor Cell Transplants (AHPCT) From Adult Unrelated Donors [Abstract]. BBMT 18 (S2), S223.

Boukouaci W, Busson M, Peffault de Latour R, Rocha V, Suberbielle C, Bengoufa D, Dulphy N, Haas P, Scieux C, Amroun H, Gluckman E, Krishnamoorthy R, Toubert A, Charron D, Socié G, Tamouza R. MICA-129 genotype, soluble MICA, and anti-MICA antibodies as biomarkers of chronic graft-versus-host disease Blood 2009 Dec 10;114(25):5216-24

Douik H, Ben Chaaben A, Attia Romdhane N, Romdhane HB, Mamoghli T, Fortier C, Boukouaci W, Harzallah L, Ghanem A, Gritli S, Makni M, Charron D, Krishnamoorthy R, Guemira F, Tamouza R. Association of MICA-129 polymorphism with nasopharyngeal cancer risk in a Tunisian population Hum Immunol 2009 Jan;70(1):45-8

Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease Lancet 2009 May 2;373(9674):1550-61

Nolting A, Dugast AS, Rihn S, Luteijn R, Carrington MF, Kane K, Jost S, Toth I, Nagami E, Faetkenheuer G, Hartmann P, Altfeld M, Alter G. MHC class I chain-related protein A shedding in chronic HIV-1 infection is associated with profound NK cell dysfunction Virology 2010 Oct 10;406(1):12-20

Viny AD, Clemente MJ, Jasek M, Askar M, Ishwaran H, Nowacki A, Zhang A, Maciejewski JP. MICA polymorphism identified by whole genome array associated with NKG2D-mediated cytotoxicity in T-cell large granular lymphocyte leukemia Haematologica 2010 Oct;95(10):1713-21



Huang SY, Chiang CH, Chen FP, Yu CL. The alteration of placental-derived soluble MHC class I chain-related protein A and B during pregnancy Acta Obstet Gynecol Scand 2011 Jul;90(7):802-7

Yoshida K, Komai K, Shiozawa K, Mashida A, Horiuchi T, Tanaka Y, Nose M, Hashiramoto A, Shiozawa S. Role of the MICA polymorphism in systemic lupus erythematosus Arthritis Rheum 2011 Oct;63(10):3058-66

Kumar V, Yi Lo PH, Sawai H, Kato N, Takahashi A, Deng Z, Urabe Y, Mbarek H, Tokunaga K, Tanaka Y, Sugiyama M, Mizokami M, Muroyama R, Tateishi R, Omata M, Koike K, Tanikawa C, Kamatani N, Kubo M, Nakamura Y, Matsuda K. Soluble MICA and a MICA variation as possible prognostic biomarkers for HBV-induced hepatocellular carcinoma PLoS One 2012;7(9):e44743

Lin D, Lavender H, Soilleux EJ, O'Callaghan CA. NF-B regulates MICA gene transcription in endothelial cell through a genetically inhibitable control site J Biol Chem 2012 Feb 3;287(6):4299-310

Sharma A, Armstrong AE, Posner MP, Kimball PM, Cotterell AH, King AL, Fisher RA, Godder K. Graft-versus-host disease after solid organ transplantation: a single center experience and review of literature Ann Transplant 2012 Dec 31;17(4):133-9

Zdrenghea MT, Telcian AG, Laza-Stanca V, Bellettato CM,

Edwards MR, Nikonova A, Khaitov MR, Azimi N, Groh V, Mallia P, Johnston SL, Stanciu LA. RSV infection modulates IL-15 production and MICA levels in respiratory epithelial cells Eur Respir J 2012 Mar;39(3):712-20

McWilliam H, Li W, Uludag M, Squizzato S, Park YM, Buso N, Cowley AP, Lopez R. Analysis Tool Web Services from the EMBL-EBI Nucleic Acids Res 2013 Jul;41(Web Server issue):W597-600

Robinson J, Halliwell JA, McWilliam H, Lopez R, Parham P, Marsh SG. The IMGT/HLA database Nucleic Acids Res 2013 Jan;41(Database issue):D1222-7

Dhir S, Slatter M, Skinner R. Recent advances in the management of graft-versus-host disease Arch Dis Child 2014 Dec;99(12):1150-7

Song GG, Kim JH, Lee YH. Associations between the major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism and susceptibility to psoriasis and psoriatic arthritis: a meta-analysis Rheumatol Int 2014 Jan;34(1):117-23


Ahmed Z, Askar M. MICA (MHC class I polypeptide-related sequence A). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5):340-348.

Leukaemia Section Short Communication





t(11;21)(p14;q22) RUNX1/KIAA1549L Akihiro Abe

Department of Hematology, Fujita Health University School of Medicine, 98 Dengakugakubo

Toyoake, Aichi 470-1192, Japan (AA)

Published in Atlas Database: October 2014

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1121p14q22ID1703.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62123/10-2014-t1121p14q22ID1703.pdf DOI: 10.4267/2042/62123


Abstract Review on t(11;21)(p14;q22) RUNX1/KIAA1549L

BL, with data on clinics, and the genes implicated.

Identity

G-banded partial karyotype of a patient with a t(11;21)(p14;q22). Arrows indicate derivative

chromosomes.Clinics and pathology

Disease

Acute myeloid leukemia (AML), AML-M1 by FAB

subtype

Phenotype/cell stem origin

CD13, CD19, CD33, CD34, and HLA-DR were

positive.

Epidemiology

This is a rare chromosomal rearrangement. A case

of MDS with t(11;21)(p14;q22) involving the

RUNX1 locus with RUNX1 gene amplification

(Moosavi et al., 2009) and a case of AML-M4 with

t(11;21)(p13;q22) (Arber et al., 2002) were

previously reported. This case is only one AML

patient characterized at molecular level to date (Abe

et al., 2012).

Clinics

A 78-year-old man suffering from bleeding

tendency and fatigue with dyspnea for one month

was diagnosed as AML.

Leukemic cells had large nuclei and little cytoplasm without azure granules.

Cytology

Blast morphology showed minimal differentiation

implicating AML M1. Leukemia cells were weakly

positive for myeloperoxidase and negative for

esterase.

Pathology

Bone marrow examination at diagnosis showed

hypocellular marrow with 57% leukemic blasts.

t(11;21)(p14;q22) RUNX1/KIAA1549L Abe A


Treatment

The patient received two courses of remission

induction chemotherapy with daunorubicin and

cytarabine, however, a complete remission was not

achieved. The leukemia cells were slow-growing in

the early period after diagnosis, so that he received

11 cycles of low dose cytarabine after induction

failure and lived for 2 years. He was died from

progression of leukemia possible with intracranial

hemorrhage.

Genes involved and proteins

KIAA1549L

Location

11p13-14

Note

KIAA1549L is also known as C11ORF41 or

C11ORF69. The function of KIAA1549L is not

known.

Northern blot analysis of several human tissues

detected two transcripts of 11 and 7.9 kb in brain

(Gawin et al., 1999). KIAA1549L indicates a

KIAA1549-like ortholog. KIAA1549 is known as a

fusion partner of BRAF in pilocytic astrocytomas

(Jones et al., 2008).

DNA/RNA

The KIAA1549L gene contains 20 exons spanning

132 kb of genomic DNA. Four transcripts are

known. Transcription orientation: telomere to

centromere.

Protein

The predicted KIAA1549L proteins contain 1849

amino acids, 199 kDa.

RUNX1

Location

21q22

DNA/RNA

Transcription orientation: telomere to centromere.

Protein

The predicted RUNX1 proteins contain 250, 453

and 480 amino acids designated as RUNX1a,

RUNX1b and RUNX1c, respectively.

All 3 proteins contain the 128-amino acid Runt

domain, but RUNX1a does not contain a

transcriptional activation domain of C-terminal

region.

Result of the chromosomal anomaly

Hybrid gene

Description

5' RUNX1-KIAA1549L 3'.

Transcript

Two types of in-frame RUNX1-KIAA1549L fusion

transcripts were detected. One was a fusion

between exon 5 of RUNX1 and exon 13 of

KIAA1549L (Type 1) and the other was between

exon 6 of RUNX1 and exon 13 of KIAA1549L

(Type 2). A reciprocal KIAA1549L-RUNX1 fusion

was not detected. Both fusion transcripts include

the region encoding Runt homology domain of

RUNX1.

References Gawin B, Niederführ A, Schumacher N, Hummerich H, Little PF, Gessler M. A 7.5 Mb sequence-ready PAC contig and gene expression map of human chromosome 11p13-p14.1. Genome Res. 1999 Nov;9(11):1074-86

Arber DA, Slovak ML, Popplewell L, Bedell V, Ikle D, Rowley JD. Therapy-related acute myeloid leukemia/myelodysplasia with balanced 21q22 translocations. Am J Clin Pathol. 2002 Feb;117(2):306-13

Jones DT, Kocialkowski S, Liu L, Pearson DM, Bäcklund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority

t(11;21)(p14;q22) RUNX1/KIAA1549L Abe A


of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7

Moosavi SA, Sanchez J, Adeyinka A. Marker chromosomes are a significant mechanism of high-level RUNX1 gene amplification in hematologic malignancies. Cancer Genet Cytogenet. 2009 Feb;189(1):24-8

Abe A, Katsumi A, Kobayashi M, Okamoto A, Tokuda M, Kanie T, Yamamoto Y, Naoe T, Emi N. A novel RUNX1-

C11orf41 fusion gene in a case of acute myeloid leukemia with a t(11;21)(p14;q22). Cancer Genet. 2012

Nov;205(11):608-11


Abe A. t(11;21)(p14;q22) RUNX1/KIAA1549L. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5):349-351.

Leukaemia Section Short Communication





t(4;17)(q12;q21) FIP1L1/RARA Adriana Zamecnikova

Kuwait Cancer Control Center, Dep of Hematology, Laboratory of Cancer Genetics, Kuwait (AZ)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0417q12q21ID1470.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62124/10-2014-t0417q12q21ID1470.pdf DOI: 10.4267/2042/62124

This article is an update of : Buijs A, Bruin M. t(4;17)(q12;q21). Atlas Genet Cytogenet Oncol Haematol 2008;12(5)


Abstract Review on t(4;17)(q12;q21) FIP1L1/RARA, with

data on clinics, and the genes implicated.

Clinics and pathology Disease

Juvenile myelomonocytic leukemia (JMML) and

acute promyelocytic leukemia (APL)

Epidemiology

Only 3 cases reported; a 1 year old male patient

with JMML (Buijs and Bruin, 2007) and 2 females

aged 77 and 90 years diagnosed with APL (Kondo

et al., 2008; Menezes et al., 2011).

Morphology of JMML. Bone marrow smears were stained with May-Grünwald-Giemsa and shown at 1000-fold

magnification. Bd=band, Bl=myelomonoblast, Eb=erythroblast, Mc=myelocyte, Mo=monocyte, Pm=promyelocyte, Se=segmented neutrophylic

granulocyte.

Evolution

Sole anomaly at diagnosis in a JMML patient that

evolved to complex karyotype at relapse: 45,XY,-

4,t(4;17)(q12;q21), add(5)(p15),del(7)(q22), -9, -

16, -17, +3mar[19]/46,XY[5].

Karyotype of patients with APL:

47,XX,t(4;17)(q12;q21),+8 (Menezes et al., 2011)

and 44,X,add(X)(p?),-2,t(4;17)(q12;q21),-4,-16

(Kondo et al., 2008).

Prognosis

Unknown, as only rare cases reported.

The patient with JMML succumbed after two SCT.

In patients with APL, FIP1L1-RARA had an ATRA

response similar to that of PML-RARA.

Cytogenetics

Partial GTG-banded karyotype of t(4;17)(q12;q21).

t(4;17)(q12;q21) FIP1L1/RARA Zamecnikova A


FISH analysis using probe LSI RARA DC resulting in a fusion signal on chromosome 17 band q21, with a split 5' RARA red signal on der(17) and a 3' RARA green signal on der(4) (left panel). FISH analysis narrowing the 4q12 breakpoint to the proximity of FIP1L1 by using 4q12 specific BAC probes RP11-120K16/RP11-317M1 with a fusion signal on chromosome 4 band q12, with

RP11-120K16 hybridizing to der(4)(green) and RP11-317M1 hybridizing to der(17)(red) (right panel).

Variants

In APL 17q21 RARA frequent rearrangement in:

t(15;17)(q22;q21), fused with PML; in related

translocations, rarely observed, involve a common

breakpoint in 17q21, within RARA, fused with

different partners, in: t(11;17)(q23;q21), fusion

with PLZF, t(5;17)(q35;q12), fusion with NPM1, in

t(11;17)(q13;q21), fusion with NUMA and in

dup(17)(q12q21), fusion with Stat5b. In

myeloproliferative disease CEL (Chronic

eosinophilic leukemia) 4q12 FIP1L1

rearrangement: fusion to PDGFRA due to 800 Kb

interstitial deletion.

Genes involved and proteins

FIP1L1

Location

4q12

Protein

FIP1L1 is a subunit of the cleavage and

polyadenylation specific factor (CPSF) complex

that binds to U-rich elements via arginine-rich RNA

binding motif and interacts with poly(A)polymerase

(PAP).

RARA

Location

17q21

Protein

Wide expression; nuclear receptor; binds specific

DNA sequences: HRE (hormone response

elements); ligand and dimerization domain; role in

growth and differentiation.

Result of the chromosomal anomaly

Hybrid gene

Description

In-frame fusion of exon 15 of FIP1L1 to exon 3 of

RARA (Buijs and Bruin, 2007; Kondo et al., 2008)

or with exon 13 of the FIP1L1 gene (Menezes et al.,

2011).

Transcript

5'FIP1L1-3'RARA and 5'RARA-3'FIP1L1.

Fusion protein

Description

The fusion mRNA would encode a 832 amino acids

FIP1L1/RARA chimeric protein containing the 428

amino-terminal amino acids of FIP1L, including the

FIP homology domain and 403 carboxyl-terminal

amino acids of RARA, including the DNA and

ligand binding domains, with replacement of

FIP1L1 amino acid 429 (Valine) and RARA amino

acid 60 (Threonine) into an Alanine.

Oncogenesis

All known chimeric RARA fusion proteins provide

additional homodimerization motifs, promoting

formation of chimeric homodimers and thereby

removing requirement of RXR for RARA to bind

DNA.

t(4;17)(q12;q21) FIP1L1/RARA Zamecnikova A


FIP1L1: Conserved FIP domain; RARA; DBD DNA binding domain, LBD ligand binding domain.

The homodimerization ability of RARA fusion

proteins is critical for leukemic transformation.

Recently, it was shown in a murine system that

retroviral transduced FIP1L1/PDGFRA mediated

transformation in vitro and in vivo, is FIP1L1

independent and results from disruption of the

autoinhibitory JM domain of PDGFRA.

However, observations using retroviral transduced

FIP1L1/PDGFRA and FIP1L1/PDGFRA with an

N-terminal deletion of the FIP1L1 moiety showed

differences with respect to cytokine-independent

colony formation and activation of multiple

signalling pathways in human primary

hematopoietic precursor cells, indicating that

FIP1L1 contributes to FIP1L1/PDGFRA resulting

in a myeloproliferative phenotype.

Therefore the function of the FIP1L1 moiety

remains to be resolved

To be noted

Note

We report on reciprocal FIP1L1/RARA fusion

transcripts resulting from a novel t(4;17)(q12;q21)

in a case of juvenile myelomonocytic leukemia

(JMML).

JMML is a pediatric myeloproliferative disease

(MPD), characterized by proliferation of

granulocytic and monocytic lineages.

17q12 RARA was demonstrated to be involved in

t(15;17)(q22;q21), resulting in a PML/RARA

fusion transcript.

PML/RARA t(15;17) is the hallmark of acute

promyelocytic leukemia (APL), characterized by a

differentiation arrest of abnormal promyelocytes.

Variant rearrangements involving 17q21 RARA in

APL and APL-like (APL-L) disease are

PLZF/RARA t(11;17)(q23;q21), NPM1/RARA

t(5;17)(q35;q21), NUMA/RARA

t(11;17)(q13;q21), STAT5b/RARA der(17) and

t(3;17)(p25;q21). 4q12 FIP1L1 is fused to

PDGFRA as a result of a del(4)(q12q12) in

myeproliferative disorder CEL.

References Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P, Williams IR, Gilliland DG, Cools J. Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8078-83

Buijs A, Bruin M. Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia. Leukemia. 2007 May;21(5):1104-8

Foster DA. Regulation of mTOR by phosphatidic acid? Cancer Res. 2007 Jan 1;67(1):1-4

Kondo T, Mori A, Darmanin S, Hashino S, Tanaka J, Asaka M. The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia. Haematologica. 2008 Sep;93(9):1414-6

Menezes J, Acquadro F, Perez-Pons de la Villa C, García-Sánchez F, Álvarez S, Cigudosa JC. FIP1L1/RARA with breakpoint at FIP1L1 intron 13: a variant translocation in acute promyelocytic leukemia. Haematologica. 2011 Oct;96(10):1565-6


Zamecnikova A. t(4;17)(q12;q21) FIP1L1/RARA. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5):352-354.

Deep Insight Section





The nuclear pore complex: structure and function Vincent Duheron, Birthe Fahrenkrog

Institute for Molecular Biology and Medicine, Université Libre de Bruxelles, 6041 Charleroi, Belgium


Online updated version : http://AtlasGeneticsOncology.org/Deep/NuclearPoreFunctionID20139.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62125/10-2014-NuclearPoreFunctionID20139.pdf DOI: 10.4267/2042/62125


Abstract Forkhead box P3 (FOXP3), a gene member of the forkhead/winged-helix family of transcription regulators, is

Nuclear pore complexes (NPCs) are large multi-protein complexes, which are embedded in the nuclear envelope

and which are regulating the molecular exchange between the nucleus and the cytoplasm. While electron

microscopy and cryo-electron tomography studies have provided high-resolution pictures of the NPC structure as

entity, the challenge nowadays is to elucidate the organization and the functions of nuclear pore proteins

(nucleoporins or Nups) inside and outside the NPC. Nucleoporins are not only involved in nucleocytoplasmic

transport, but in an increasing number of other cellular processes, such as kinetochore organization, cell cycle

regulation, DNA repair, and gene expression. The implication of nucleoporins in these diverse processes links

them also to a wide variety of human diseases, such as cancer and autoimmune diseases. Here we review the

progress made in defining the molecular arrangement of nucleoporins within the NPC and use the example of

Nup153 to illustrate the versatility of individual nucleoporins and their implication in various human diseases.

Keywords: nucleus, nuclear pore complex; nucleoporins, FG repeats, nucleocytoplasmic transport, Nup153,

disease, HIV-1

1. IntroductionNuclear and cytoplasmic compartments of

interphase eukaryotic cell are separated by the

nuclear envelope (NE), which is formed from two

closely juxtaposed membranes, the outer nuclear

membrane (ONM) and the inner nuclear membrane

(INM), respectively. The ONM is continuous with

the rough endoplasmic reticulum, whereas the INM

contains unique transmembrane proteins, which

establish contacts with chromatin and the nuclear

lamina. Large multi-protein complexes known as

nuclear pore complexes (NPCs) perforated the NE

to allow molecular trafficking between the

cytoplasm and the nucleus. Nucleocytoplasmic

transport comprises passive diffusion of small

molecules and ions, as well as signal- and receptor-

mediated translocation of proteins and

ribonucleoprotein complexes that are larger than

~40 kDa (Görlich et al., 1995; Melchior et al.,

1993; Moroianu and Blobel, 1995; Moroianu et al.,

1995a; Moroianu et al., 1995b; Radu et al., 1995a;

Radu et al., 1995b; Rexach and Blobel, 1995;

Sweet and Gerace 1995; Kehlenbach et al., 1998;

Chook et al., 1999; Keminer and Peters, 1999; for

review see: Görlich and Kutay, 1999). Nuclear

transport receptors are collectively known as

karyopherins and they comprise importins and

exportins. Karyopherins recognize signal sequences

within their cognate cargoes: nuclear localization

signals (NLSs) for cargo destined for the nucleus

and nuclear export signals (NESs) for cargo that is

exported from the nucleus (Moroianu and Blobel,

1995; Moroianu et al., 1995a; Moroianu et al.,

1995b; Moroianu et al., 1996; Wen et al., 1995;

Conti et al., 1998; Feng et al., 1999). The

directionality of nucleocytoplasmic transport is

determined by the small GTPase Ran, which is

switching between its GDP- and GTP-bound states

(Melchior et al., 1993; Moore and Blobel, 1993;

The nuclear pore complex: structure and function Duheron V, Fahrenkrog B


Weis et al., 1996; Izaurralde et al., 1997; Görlich

and Kutay, 1999). RanGTP is predominantly found

in the nucleus and its binding to importins displaces

import cargo from the receptor (Görlich et al.,

1996; Izaurralde et al., 1997). The RanGTP-

importin complex is directed to the cytoplasm,

where the cytoplasmic GTPase-activating protein

RanGAP1 catalyzes GTP hydrolysis, together with

the Ran-binding proteins RanBP1 and RanBP2.

GTP hydrolysis results in the disassembly of the

RanGTP-importin complex and the subsequent

recycling of the importin for a new round of nuclear

import (Kutay et al., 1997a; for review see: Görlich

and Kutay, 1999). RanGTP furthermore forms

trimeric complexes with exportins and export

cargoes to stabilize their interaction during nuclear

export (Arts et al., 1998; Fornerod et al., 1997;

Kaffman et al., 1998; Kutay et al., 1997a; Kutay et

al., 1998). After translocation through the NPC,

cytoplasmic GTP hydrolysis allows the dissociation

of the trimeric complex and the redirection of the

exportin to the nucleus. RanGDP is reimported by

its own nuclear import receptor, NTF2 (Ribbeck et

al., 1998; Bayliss et al., 1999; Chaillan-Huntington

et al., 2000), and the GDP on Ran becomes

exchanged to GTP by the action of the chromatin-

bound Ran guanine nucleotide exchange RCC1,

which is critical to maintain the intracellular Ran

gradient (Görlich et al., 1996; Boche and Fanning,

1997; Izaurralde et al., 1997). Cargo translocation

through NPCs is a fast process with hundreds of

proteins, RNA particles, and metabolites passing

through each NPC every second (Peters et al., 1986;

Schulz and Peters, 1987; Peters et al., 1990;

Middeler et al., 1997; Ribbeck and Görlich, 2001;

Yang et al., 2004; Kubitscheck et al., 2005; Dange

et al., 2008; Siebrasse et al., 2012).

2. Nucleoporins The NPC is composed of approximately 30

different proteins, termed nucleoporins (Nups),

which are broadly conserved between yeast,

vertebrates and plants (Rout et al., 2000; Cronshaw

et al., 2002; Neumann et al., 2010). Secondary

structure predictions of nucleoporins allowed their

classification into three groups (Schwartz, 2005;

Devos et al., 2006): the first group of nucleoporins

is characterized by the presence of transmembrane

α-helices and cadherin-like domains, which mediate

the anchoring of NPCs to the NE and which

stabilize the interaction between the INM and the

ONM.

The second group is composed of nucleoporins

containing α-solenoid and β-propeller folds, which

may optimize interactions between nucleoporins as

these particular structures are mainly found in

architectural, scaffold nucleoporins. This scaffold

nucleoporins connect the transmembrane

nucleoporins to nucleoporins containing

phenylalanine-glycine (FG)-repeats, i.e. the third

group of nucleoporins (Schwartz, 2005; Devos et

al., 2006).

FG nucleoporins represent about one third of the

nucleoporins and they are characterized by the

presence of repeated clusters of FG motifs that fall

into three predominant classes: FxFG (x refers to

any residue), GLFG (L refers to leucine) and FG.

Other less frequent motifs are PAFG, PSFG and

SAFG (Devos et al., 2006; Denning and Rexach,

2007). FG motifs are separated by linker sequences,

which are typically enriched in charged and polar

amino acids and are "disorder"-associated (Dunker

et al., 2001; Denning and Rexach, 2007). The linker

sequences lack hydrophobic, "order"-associated

amino acids, so that this particular amino acid

distribution renders FG domains natively unfolded

with an absence of secondary structure (Denning et

al., 2002; Denning et al., 2003; Fahrenkrog et al.,

2002; Lim et al., 2006a).

The extend of charged amino acids varies between

individual nucleoporins and two subgroups appear

to exist: FG domains with low content of charged

amino acids, which are capable of low affinity

interactions among each other, whereas FG

domains with a high content of charged amino acids

abolish interactions with each other (Patel et al.,

2007; Yamada et al., 2010; Xu and Powers, 2013).

In this context, GLFG motifs are more susceptible

to interact with each other than other motifs (Patel

et al., 2007). The cohesiveness of FG domains and

the spacing between the FG motifs is further

dependent on the amino acid composition of the

linker sequences (Patel et al., 2007; Dolker et al.,

2010). An interaction between FG domains may

contribute to a cohesive barrier that hinders

diffusion of small proteins through the NPC

(Shulga et al., 2000; Ribeck and Görlich, 2001;

Hülsmann et al., 2012). FG nucleoporins are

located throughout the NPC (Rout et al., 2000;

Fahrenkrog et al., 2002; Walther et al., 2002;

Paulillo et al., 2005; Schwarz-Herion et al., 2007;

Chatel and Fahrenkrog, 2012) and they are

mediating the interaction to nuclear transport

receptors. Crystal structures have shown that the

interaction between FG repeats and transport

receptors mainly involves the Phe residues of the

FG repeats, together with the flanking Gly residues

that provide conformational flexibility, and

hydrophobic residues of the receptor (Quimby et

al., 2001; Fribourg et al., 2001; Bayliss et al.,

2002a; Bayliss et al., 2002b; Liu and Stewart, 2005;

Vognsen et al., 2013). Karyopherins possess several

FG-binding sites and their translocation through the

NPC is accomplished due to multiple and rapid

binding events to the FG-nucleoporins (Rexach and

Blobel, 1995; Kutay et al., 1997; Bayliss et al.,

2000; Allen et al., 2001; Gilchrist et al., 2002;

Tetenbaum-Novatt et al., 2012). While originally it

was assumed that an "affinity gradient" between

karyopherins and nucleoporins determines



translocation from the cytoplasmic filaments to the

nuclear basket (Ben-Efraim and Gerace, 2001;

Pyhtila and Rexach, 2003), it has now been shown

that only FG-nucleoporins that are symmetrically

localized to both sides of the NPC are essential for

translocation and cell viability, whereas the

asymmetric FG-nucleoporins are dispensable for

transport (Strawn et al., 2004). Yeast NPCs can

accommodate the loss of 50% of their FG-repeats

with only little effect on nucleocytoplasmic

transport or NPC permeability. Moreover, Zeitler et

al. were able to alter or invert the asymmetric

distribution of FG-nucleoporins without altering

nucleocytoplasmic transport (Zeitler et al., 2004).

The disordered configuration of FG-nucleoporins

and the transient, dynamic interactions within the

NPC make the elucidation of the nucleocytoplasmic

transport mechanisms difficult. Numerous

translocation models have been elaborated, such as

the Brownian affinity/virtual gating/polymer brush

model (Rout et al., 2000; Rout et al., 2003; Lim et

al., 2006; Lim et al., 2007), the selective

phase/hydrogel model (Ribbeck and Görlich, 2002;

Frey et al., 2006; Frey et al., 2007), the reduction of

dimensionality model (Peters, 2005; Moussavi-

Baygi et al., 2011), and the forest model (Yamada

et al., 2010). Details of the models are discussed in

depth in several excellent recent review articles

(Tetenbaum-Novatt and Rout, 2010; Wente and

Rout, 2010; Lim and Deng, 2009).

3. NPC architecture Nucleoporins assemble into distinct subcomplexes

(Fig. 1A), which can be isolated as such from

interphase NPCs and frequently from disassembled

mitotic NPCs as well. These nucleoporin

subcomplexes serve as building blocks for the NPC

(Matsuoka et al., 1999; Allen et al., 2002;

Suntharalingam and Wente, 2003; Schwartz, 2005).

Electron microscopic and tomographic analyses of

NPCs from different species, such as yeast,

Xenopus, and human, have demonstrated that,

despite the large evolutionary distance between

these species, the basic structural organization of

the NPC is evolutionary conserved (Xenopus:

Hinshaw et al., 1992; Akey and Radermacher,

1993; Stoffler et al., 2003; Frenkiel-Krispin et al.,

2010; human: Maimon et al., 2012; Bui et al., 2013;

yeast: Fahrenkrog et al., 1998; Rout et al., 2000;

Kiseleva et al., 2004; Dictyoselium: Beck et al.,

2004; Beck et al., 2007; Grossman et al., 2012).

Accordingly, the NPC consists of an eight-fold

symmetric central framework, eight cytoplasmic

filaments and a nuclear basket (Fig. 1B). The

central framework has an hourglass-like shape and

is composed of three connected rings: a central

spoke ring sandwiched between a cytoplasmic ring

and a nuclear ring. The spoke ring resides within

the NE and is anchored to the region where the

inner and outer nuclear membranes fuse. Eight

cytoplasmic filaments are attached to the

cytoplasmic ring, while the nuclear ring is also

decorated with eight filaments that join into a distal

ring, thereby forming the NPC's nuclear basket

(Fahrenkrog and Aebi, 2003; Beck and Medalia,

2008; Grossman et al., 2012; Maimon et al., 2012).

Among the NPC subcomplexes, the Nup107-160

complex is the most studied and best characterized

one due to its pivotal role for NPC assembly. The

Nup107-160 complex is composed of nine

nucleoporins, i.e. Nup160, Nup133, Nup107,

Nup96, Nup85, Nup43, Nup37, Sec13, and Seh1

(Belgareh et al., 2001; Vasu et al., 2001) and it is

usually associated with the putative transcription

factor Elys/Mel-28 (Rasala et al., 2006;

Szymborska et al., 2013).

Depletion of any member of the Nup107-160

complex leads to defects in NPC assembly

(Boehmer et al., 2003; Harel et al., 2003; Walther et

al., 2003).

The Nup107-160 complex is symmetrically located

to both sides of the NPC (Belgareh et al., 2001;

Vasu et al., 2001; Bui et al., 2013; Szymborska et

al., 2013) and EM analysis of the isolated Nup107-

160 complex and its yeast homologue, the Nup84p

complex, has revealed that the complex adopts a Y-

shaped architecture (Fig. 2A) (Siniossoglou et al.,

1996; Siniossoglou et al., 2000; Lutzmann et al.,

2002; Kampmann and Blobel, 2009; Bui et al.,

2013).

The relative positions of each nucleoporin within

the Y complex are known (Kampmann and Blobel,

2009; Bui et al., 2013), whereas its orientation

within the NPC is not ultimately clear.

Three main models are discussed: (1) the fence

model predicts that 32 copies of the Nup84p

complex are organized in four octameric rings,

which are packed in antiparallel orientation, and

which are linked by vertical hetero-octamers of

either Nup85p-Seh1p or Nup145p-Sec13p (Fig. 2B)

(Debler et al., 2008); (2) the lattice model predicts

that the Nup84p complex resides on the

cytoplasmic and nuclear side of the NPC,

sandwiching the Nic96p complex (see below), with

the long axis of Nup84p complex positioned almost

parallel to the nucleocytoplasmic transport axis

(Fig. 2C) (Brohawn and Schwartz, 2009b); (3) the

head-to-tail model suggests that Nup84p complexes

are arranged head-to-tail into two antiparallel rings

on the cytoplasmic and nuclear face of the NPC

(Fig. 2D) (Alber et al., 2007a; Seo et al., 2009).

Recent advances in light microscopy confirmed the

head-to-tail octameric ring arrangement of the

Nup107-160 complex directly in cells (Szymborska

et al., 2013) and electron tomography data indicate

that Nup107-160 complexes assemble at both faces

of the NPC as paired octameric rings with a shift of

about 11 nm towards each other, which in turn

appears to be important for the structural plasticity

of the NPC (Bui et al., 2013).



Figure 1. Architecture of the nuclear pore complex (NPC) and nucleoporin (Nup) localization. (A) Schematic overview of the subcomplex organization of the NPC in human (left) and yeast (right). Nups can be subdivided into different subgroups

depending on their localization: transmembrane Nups (white), cytoplasmic filaments and associated Nups (blue), outer rings Nups (green), adaptator Nups (yellow), channel Nups (pink) and nuclear basket Nups (red). (B) Schematic representation of the

NPC architecture and (C) dimensions in Xenopus oocytes, human and yeast cells.



Figure 2. Position of the human Nup107-160 complex within the 3D architecture of the NPC. (A) Schematic representation of the organization of the human Nup107-160 complex. (B) Schematic representation of the fence model. (C) Schematic representation

of the lattice model. (D) Schematic representation of two possible orientations of the head-to-tail model. (E) Position of the two hNup107-160 octameric rings in the cytoplasmic ring. (A-D are reproduced from Szymborska et al. 2013; E is reproduced from

Bui et al. 2013).



Sandwiched between the Nup107-160 complex and

the cytoplasmic and nuclear ring is the Nup93

complex, which is composed of five nucleoporins,

i.e. Nup93, Nup205, Nup188, Nup155 and

Nup35/53, and it is evolutionary conserved (Grandi

et al., 1995; Schlaich et al., 1997; Grandi et al.,

1997; Miller et al., 2000; Galy et al., 2003;

Hawryluk-Gara et al., 2005; Hawryluk-Gara et al.,

2008; Theerthagiri et al., 2010; Amlacher et al.,

2011; Sachdev et al., 2012; Vollmer and Antonin,

2014). It occupies a central position in the NPC

architecture, serving as a link between the different

nucleoporin subcomplexes within the NPC scaffold.

Hence the Nup93 complex can potentially link the

NPC to the NE via Nup35/53 and Nup155: both

interact with the transmembrane nucleoporin Ndc1

and Nup155 additionally with Pom121 (Mansfeld et

al., 2006; Onischenko et al., 2009; Mitchell et al.,

2010; Eisenhardt et al., 2014). No direct interaction

between the Nup107-160 and the Nup93 complex

has been demonstrated in vertebrates, but for the

yeast complexes (Lutzmann et al., 2005),

suggesting that their vertebrate homologues bind

each other as well.

The Nup93 complex is also interacting with

nucleoporins of the Nup62 complex via the N-

terminal region of Nup93 and Nup62 (Grandi et al.,

1997; Sachdev et al., 2012), which links the Nup93

complex to the channel nucleoporins Nup62,

Nup58, Nup54 and Nup45 (Finlay et al., 1991;

Guan et al., 1995; Vasu and Forbes, 2001; Xenopus

homologues: Macaulay et al., 1995; yeast

homologues: Grandi et al., 1993). The FG-

nucleoporins of the Nup62 complex are believed to

project their FG-domains towards the center of the

NPC channel thereby contributing to

nucleocytoplasmic transport and the NPC

permeability barrier (Finlay et al., 1991; Paschal

and Gerace, 1995; Clarkson et al., 1996; Hu et al.,

1996; Yoshimura et al., 2013). How the peripheral

NPC structures, the cytoplasmic filaments and the

nuclear basket, are exactly linked to the NPC

scaffold remains to be seen.

While the comparison of NPCs from different

organisms revealed a shared global architecture,

variations especially in the height of the central

framework were observed (Fig. 1C). For instance,

the central framework of NPCs from Xenopus

laevis are ~ 95 nm high with an outer diameter of ~

125 nm (Frenkiel-Krispin et al., 2010; Stoffler et

al., 2003), while human NPCs have a central

framework with a height of ~ 85 nm and an outer

diameter of ~ 120 nm (Maimon et al., 2012; Bui et

al., 2013). NPCs from yeast and Dictyoselium

discoideum are more compact with a central

framework of ~ 60 nm in height and an outer

diameter of ~ 120 nm (Fahrenkrog et al., 1998;

Yang et al., 1998; Beck et al., 2004; Beck et al.,

2007; Kiseleva et al., 2004; Frenkiel-Krispin et al.,

2010). Closer analyses of the central spoke ring

revealed a similar thickness (~ 35 nm) of this ring

in different species, indicating that the size

differences within the central framework arise from

species-specific variations in the arrangements of

the cytoplasmic and nuclear rings (Frenkiel-Krispin

et al., 2010). Despite these differences in the

dimensions of the central framework, the diameter

of the central pore in the mid plane of the NE is

about 40 and 50 nm (Fahrenkrog et al., 1998; Yang

et al., 1998; Stoffler et al., 2003; Beck et al., 2007,

Fiserova et al., 2009; Frenkiel-Krispin et al., 2010;

Bui et al., 2013), which is close to the size limit of

39 nm in diameter for cargo translocation (Panté

and Kann, 2002). Besides the central pore,

metazoan NPCs exhibit peripheral channels of ~ 5-

10 nm in diameter (Hinshaw et al., 1992; Akey and

Radermacher, 1993; Yang et al., 1998; Stoffler et

al., 2003; Beck et al., 2007; Maimon et al., 2013).

These peripheral channels seem to be absent in

yeast NPCs likely due to the smaller size of the

central spoke complex (Yang et al., 1998). As of

today, the function of these peripheral channels is

not ultimately clear and controversially discussed

(Hinshaw et al., 1992; Akey, 1995; Soullam and

Worman, 1995; Kiseleva et al., 1998; Danker et al.,

1999; Shahin et al., 2001; Stoffler et al., 2003;

Ohba et al., 2004; Frenkiel-Krispin et al., 2010).

4. The nucleoporin Nup153: domain organization and localization The nucleoporin Nup153 is a constituent of the

NPC's nuclear basket (Pante et al., 1994; Pante et

al., 2000; Walther et al., 2001; Fahrenkrog et al.,

2002; Hase and Cordes, 2003), and it is, based on

its amino acid sequence, comprised of roughly three

major domains: (i) a N-terminal domain, which

further includes a nuclear envelope targeting

cassette (NETC; amino acids 1-144), a nuclear pore

association region (NPAR; amino acids 39-339)

and a RNA binding domain (RBD; amino acids

250-400) (Bastos et al., 1996; Enarson et al., 1998;

Ball et al., 2004), (ii) a central zinc finger domain

and (iii) a FG-rich C-terminal domain (for review

see: Ball and Ullman, 2005) (Fig. 3A). The zinc-

finger domain of Nup153 binds DNA in vitro

(Sukegawa and Blobel, 1993) as well as RanGDP

and RanGTP, albeit with a preference for the GDP-

bound form (Higa et al., 2007, Schrader et al.,

2008; Partridge et al., 2009). The cellular functions

of these interactions have thus far remained elusive.

Important for NE breakdown in reconstituted nuclei

from Xenopus egg extracts, however, is the

recruitment of the coatomer COPI complex, a major

participant of membrane remodeling, to NPCs via

Nup153's zinc-finger domain (Liu et al., 2003;

Prunuske et al., 2006). The FG-domain of Nup153

is known to bind several nuclear transport factors,

such as importin β, transportin and NXF1, which is

important for Nup153's role in nucleocytoplasmic



transport (Shah et al., 1998; Moroianu et al., 1995;

Moroianu et al., 1997; Nakielny et al., 1999; Bachi

et al., 2000; Brownawell and Macara, 2002;

Kuersten et al., 2002; Walther et al., 2003). The FG

domain of Nup153 is natively unfolded and has a

length of about 800 nm, when fully extended (Lim

et al., 2006). The actual conformation of the FG

domain within the NPC is unknown: it might adapt

the form of a polymer brush that acts as entropic

barrier, which transiently collapses to a more

compact conformation upon interaction with

transport receptors, such as importin β (Lim et al.,

2006; Lim et al., 2007). Alternatively, Nup153's

FG-domain might form a hydrogel as seen at high

concentrations in vitro (Milles et al., 2011; Milles et

al., 2013), in which only transport receptors and

transport complexes remain soluble (Ribbeck and

Görlich, 2002; Frey et al., 2006; Frey and Görlich,

2007). Or a combination of both (Milles and

Lemke, 2011), as it has been shown for the yeast

nucleoporin Nsp1p (Ader et al., 2010).

The association of Nup153 with the nuclear basket

of the NPC (Cordes et al., 1993; Pante et al., 1994)

is rather complex, which became evident from the

application of domain-specific antibodies against

Nup153 in combination with immuno-EM analyses.

Accordingly, the N-terminal domain locates to the

nuclear ring moiety of the nuclear basket (Pante et

al., 2000; Walther et al., 2001; Fahrenkrog et al.,

2002), whereas the zinc-finger domain is found at

the distal ring (Fahrenkrog et al., 2002). Nup153's

FG-domain was detected all over the nuclear basket

and occasionally on the cytoplasmic side of the

NPC, suggesting a high mobility of this domain

(Nakielny et al., 1999; Fahrenkrog et al., 2002;

Paulillo et al., 2005; Paulillo et al., 2006; Lim et al.,

2007) (Fig. 3B). Not only the FG-domain of

Nup153 appears to be mobile, but the entire

protein: fluorescent recovery after photobleaching

(FRAP) experiments have revealed that GFP-

tagged Nup153 is highly dynamic and shuffles

between a NPC-associated and a nucleoplasmic

population (Daigle et al., 2001; Rabut et al., 2004;

Griffis et al., 2004). Nup153's mobility is dependent

on active transcription, which suggests that Nup153

may associate with mRNA cargoes to facilitate their

recruitment to the NPC (Griffis et al., 2004).

Binding to mRNA might occur either directly via

the N-terminal RNA binding domain (Ball et al.,

2004) or via the mRNA export factor NXF1, which

binds the C-terminal FG-domain of Nup153 (Bachi

et al., 2000).

Figure 3. Nup153 domain organization and localization. (A) Schematic representation of Nup153 domain architecture with the N-terminal domain (red), the zinc finger domain (blue) and the C-terminal FG-rich domain (green). The N-terminal domain contains the nuclear envelope targeting cassette (NETC; amino acids 1-144; purple), the nuclear pore association region (NPAR; amino

acids 39-339; yellow) and the RNA binding domain (RBD; amino acids 250-400; orange). Some of the known interaction partners of Nup153 are represented near the region of Nup153 they are described to interact with. (B) Domain localization of Nup153 with

the N-terminal domain localized at the ring moiety of the basket, the zinc finger domain localized to the distal ring of the basket and the FG-rich C-terminal domain was detected at the nuclear ring moiety and the distal ring of the basket, but also occasionally

at the cytoplasmic side of the NPC, showing its high mobility. c:cytoplasm; n: nucleus. (B is reproduced from Fahrenkrog et al., 2002).



5. Nup153 assembly into nuclear pores The NE of eukaryotic cells disassembles at the end

of mitotic prophase, which is accompanied with

NPC disassembly. NPC reassembly starts in late

anaphase/early telophase in a highly ordered

process during which Nup153 belongs to the early

recruited nucleoporins (Bodoor et al., 1999;

Haraguchi et al., 2000; Daigle et al., 2001; Dultz et

al., 2008). Nup153 incorporation in the reforming

NPC requires the Nup107-160 complex and

depletion of this complex impairs Nup153

recruitment to NPCs (Boehmer et al., 2003;

Walther et al., 2003; Harel et al., 2003; Krull et al.,

2004). Nup153 recruitment to the newly reforming

NPC might occur in two phases: a first pool of

Nup153 accumulates at the periphery of

chromosomes at the end of anaphase (Bodoor et al.,

1999; Haraguchi et al., 2000; Dultz et al., 2008),

shortly after Nup107-160 recruitment (Dultz et al.,

2008), while a second and major pool of Nup153

associates with the NPC later in telophase (Dultz et

al., 2008), at the same time as the nuclear lamina

(Smythe et al., 2000). The assembly and stable

association of Nup153 with the NE and NPCs is in

fact dependent on the lamina and mutations in

lamin A have been shown to displace Nup153 from

NPCs (Smythe et al., 2000, Hübner et al., 2006).

NPCs lacking Nup153 are more mobile within the

NE (Walther et al., 2001), suggesting that a

Nup153-lamina interaction is important for NPC

anchoring in the NE. Consistently, Nup153 was

found to bind lamin B3 (also known as lamin LIII)

from Xenopus egg extracts (Smythe et al., 2000)

and recombinant human lamin A and lamin B1 (Al

Haboubi et al., 2011). Moreover, Nup153 depletion

from HeLa cells altered the localization of lamin

A/C and Sun1, an INM protein that binds to lamin

A (Zhou and Pante, 2010), which coincided with a

rearrangement of the cytoskeleton and a modified

cell morphology (Zhou and Pante, 2010).

The early recruited pool of Nup153 might be

important for the reformation of a functional NPC

and the correct recruitment of other nucleoporins to

the NPC. Along this line depletion of Nup153 from

Xenopus egg extracts resulted in the loss of several

nucleoporins from the nuclear basket, amongst

others Tpr (Walther et al., 2001). Tpr is thought to

be the central architectural element of the nuclear

basket (Krull et al., 2004) and is lately recruited

during NPC reassembly (Bodoor et al., 1999;

Haraguchi et al., 2000). Consistently, Nup153

localization to the NPC is not Tpr dependent (Frosst

et al., 2002; Hase and Cordes, 2003), whereas the

importance of Nup153 for Tpr recruitment is

controversial: Nup153 depletion lead to a complete

absence of Tpr from the NE on the one hand (Hase

and Cordes, 2003), but not in other cases (Lussi et

al., 2010; Mackay et al., 2010; Umlauf et al., 2013).

In contrast to that, it is without any doubt that the

association of Nup50 with NPCs necessitates the

presence of Nup153 (Hase and Cordes, 2003;

Mackay et al., 2010). Nup50 is a mobile

nucleoporin associated with the nuclear basket

(Guan et al., 2000; Smitherman et al., 2000) and its

recruitment to reforming NPCs is closely associated

with Nup153's with a similar, biphasic recruitment

in ana- and telophase (Dultz et al., 2008).

6. Versatile functions of Nup153 Nup153 participates in nucleocytoplasmic transport

via its FG domain, which interacts with numerous

transport receptors such as importin β (Moroianu et

al., 1995; Shah et al., 1998), transportin (Shah and

Forbes, 1998), importin-5 (Yaseen and Blobel,

1997) and importin-7 (Walther et al., 2003), as well

as with the nuclear export receptors CRM1

(Nakielny et al., 1999), exportin-5 (Brownawell and

Macara, 2002), exportin-t (Kuersten et al., 2002)

and NXF1 (Bachi et al., 2000). Moreover, Nup153

binds import adapter proteins, such as importin α

(Moroianu et al., 1997) and the specialized nuclear

import receptor for Ran, NTF2 (Cushman et al.,

2004), suggesting that Nup153 is a decisive player

in many transport pathways. The high mobility of

Nup153's FG domain and its spread distribution

throughout the NPC (Fahrenkrog et al., 2002;

Paulillo et al., 2005; Lim et al., 2006; Lim et al.,

2007) may promote the translocation of nuclear

import complexes to the nuclear side of the NPC

(Ogawa et al., 2012) and/or promote the entry of

nuclear export complexes to the NPC (Soop et al.,

2005).

Because of the key position of the NPC at the

interface between the cytoplasm and the nucleus, it

became evident that nucleoporins either directly or

indirectly participate in numerous cellular

processes, both in interphase and mitosis. Not

surprisingly, Nup153 is therefore essential for cell

viability (Harborth et al., 2001; Galy et al., 2003)

and alterations in Nup153 expression impair

numerous cellular pathways by altering the

localization of a large number of factors. For

example, Nup153 contributes to gene expression

via micro RNAs and small interfering RNAs, as it

is important for the nuclear localization of Dicer1,

the protein that cuts double stranded RNAs (Ando

et al., 2011). Moreover, in Drosophila

melanogaster and in human cells Nup153 is

required for correct dosage compensation of the X-

chromosome (Mendjan et al., 2006; Vaquerizas et

al., 2010). Nup153 directly binds chromatin on

large nucleoporin-associated regions, which

probably promotes the formation of an open

chromatin environment (Vaquerizas et al., 2010).

Nup153 is critical for the nuclear localization of

53BP1, a mediator protein in DNA damage

response (DDR), to DNA double strand breaks

(DSBs) (Wang et al., 2002). Cells depleted for

Nup153 have an increased sensitivity to DSB

inducing drugs, which is in part due to a



cytoplasmic mislocalization of 53BP1 (Lemaitre et

al., 2012; Moudry et al., 2012). Furthermore,

Nup153 depletion compromised the

phosphorylation of the two cell cycle checkpoint

kinases CHK1 and CHK2, suggesting an improper

activation of the G2/M checkpoint, and it promotes

the use of the homologous recombination pathway

over non-homologous end joining to repair DSBs

(Lemaitre et al., 2012). Nup153 becomes

phosphorylated by the Ataxia telangiectasia

mutated (ATM) kinase, a key kinase during DSB

repair (Wan at al., 2013). ATM-mediated

phosphorylation of Nup153 provokes the

interaction between Nup153 and exportin-5, which

in turn promotes the nuclear export of pre-miRNAs

in response to DNA damage (Zhang et al., 2011;

Wan at al., 2013). The implication of miRNAs in

DDR is still poorly understood on a mechanistic

level, but it is known that a loss of Dicer and

miRNAs resulted in increased levels of DNA

damage (Wan et al., 2011).

Nup153 is not only impacting cellular processes

due to its central role in nucleocytoplasmic

transport, but also due to direct interactions with

numerous partners, such as transcription factors

(Zhong et al., 2005; Xu et al., 2002), signaling

molecules (Nybakken et al., 2005), membrane

remodeling proteins (Liu et al., 2003; Prunuske et

al., 2006), and SUMO specific proteases (Chow et

al., 2012). SUMOylation is a post-translational

modification characterized by the addition of a

small ubiquitin-like peptide on target proteins to

modulate their activity (for review see: Wang and

Dasso, 2009). Like ubiquitination, SUMOylation

occurs through a three-step enzymatic cascade,

which requires the action of an ATP-dependent E1

activating enzyme, an E2 conjugating enzyme and a

SUMO-specific E3 ligase. SUMOylation is a

reversible process and SUMO removal is catalyzed

by SUMO-specific isopeptidases SENPs, two of

which, SENP1 and SENP2, are located at the NE

and NPCs (Hang and Dasso, 2002; Zhang et al.,

2002; Bailey and O'Hare, 2004; Chow et al., 2012;

Cubenas-Potts et al., 2013). SENP1 and SENP2

directly interact with Nup153, suggesting that

Nup153 is responsible for their NE localization and

that it might be implicated in the deSUMOylation

of proteins (Hang and Dasso, 2002; Chow et al.,

2012; Cubenas-Potts and Matunis, 2013).

Nup153 not only has functions in interphase, but

also in mitosis. Its role in mitosis might be at least

in part due to its direct interaction with the spindle

assembly checkpoint (SAC) protein Mad1 (Lussi et

al., 2010). The SAC assures correct chromosome

segregation at the metaphase-anaphase transition

(see review Lara-Gonzalez et al., 2012) and

overexpression of Nup153 leads to a SAC override

and partial mislocalization of Mad1, which

coincides with chromosome mis-segregation,

multipolar spindle formation, multinucleation and

cytokinesis failure (Lussi et al., 2010). Cytokinesis,

the final step of mitosis, is also hampered by

siRNA-mediated depletion of Nup153 (Mackay et

al., 2009; Lussi et al., 2010).

Nup153 depletion causes mislocalization of Aurora

B kinase, which is regulating many mitotic

processes (see review van der Waal et al., 2012),

during cytokinesis.

This mislocalization of Aurora B leads to the

activation of the so-called abscission checkpoint

and consequently abscission delay and an increased

number of cells in cytokinesis (Mackay et al., 2009;

Mackay et al., 2010; Lussi et al., 2010). The

underlying molecular mechanism that leads to the

activation of the abscission checkpoint remains to

be elucidated.

7. Nup153-related disorders Because of the pivotal role of NPCs for

nucleocytoplasmic exchange, alterations in NPC

components and/or nucleocytoplasmic transport

have a strong impact on cell growth and survival.

Therefore, it is not surprising that nucleoporins and

likewise Nup153 are implicated in a large number

of disorders, such as cancer and autoimmune

disease (Table 1). Increased expression of Nup153

due to a 6p22 genomic translocation was detected

in urothelial carcinoma and retinoblastoma (Orlic et

al., 2006; Heidenblad et al., 2008). Moreover, in a

screen for pancreatic cancer genes, Nup153 was

found amplified in the pancreatic cell line PL5

(Shain et al., 2013).

This study suggested an oncogenic function for

Nup153 by modulating the TGF-β signaling

pathway.

Nup153 is known to regulate the intracellular

distribution of the TGF-β signal transducer SMAD2

(Xu et al., 2002). It stoichiometrically competes

with FAST1, a nuclear retention factor for SMAD2,

and Nup153 up-regulation leads to an increased

cytoplasmic localization of SMAD2, which disrupts

TGF-β signaling and may enforce proliferation

(Shain et al., 2013). Nup153 is furthermore

important for tumor cell migration (Zhou and Pante,

2010). Depletion of Nup153 from HeLa cells and

the breast cancer cell line MDA-231, respectively,

induced rearrangements of the actin cytoskeleton

and microtubules. The alterations of the

cytoskeleton led to impaired cell migration and

polarization of MDA-231 cells and fibrosarcoma

HT1080 cells (Zhou and Pante, 2010).

Further work is necessary to address the molecular

details of Nup153's role in cancer biology.

Small nucleotide polymorphisms (SNPs) in

NUP153 were found associated with disorders due

to hyperbilirubinemia (Datta et al., 2012) and

schizophrenia (Lin et al., 2009).

The transport of biliverdin reductase, an important

enzyme for bilirubin conjugation, is affected by a

SNP near the NUP153 locus on chromosome 6.



Table 1. Summary of human disorders involving nucleoporins.

This leads to increased levels of unconjugated

bilirubin, which in turn is associated with severe

disorders, such as bilirubin encephalopathy and

Gilbert's syndrome (Datta et al., 2012).

Autoantibodies against Nup153 were found in sera

from patients suffering from various autoimmune

diseases, such as systemic lupus erythematosis,

autoimmune thyroiditis, hepatitis B and hepatitis C

virus (HBV and HCV, respectively) infections

(Nesher et al., 2001; Enarson et al., 2004). To

explain the presence of these Nup153

autoantibodies some investigators suggested a

molecular mimicry mechanism. Sera from patients

with various autoimmune diseases possess

antibodies against HBV DNA polymerase subtype

adr (Gregorio et al., 1999). Surprisingly, sera from

patients with chronic HBV infection react with the

peptide 827-846 of Nup153. This peptide sequence

of Nup153 presents similarities to residues 57-76 of

HBV DNA polymerase, which may lead to cross-

reactions between the Nup153 peptide 827-846 and

antibodies directed against the HBV DNA

polymerase peptide 57-76 (Gregorio et al., 1999).

As mentioned earlier, Nup153 can directly interact

with the Ig-fold domain of nuclear lamins (Smythe

et al., 2000; Al Haboubi et al., 2011).



Laminopathies are disorders caused by mutations in

the LMNA gene, often localized in the Ig-fold

domain of the lamin A protein (Goldman et al.,

2004; Worman and Bonne, 2007). These mutations

reduce the population of Nup153 present at the NE

maybe by impairing Nup153-lamin interaction or

by promoting accumulation of Nup153 at mutated

lamin A aggregates (Hübner et al., 2006). This lack

of Nup153 at the nuclear periphery might

contribute to a compromised nuclear protein import

(Busch et al., 2009).

8. Nup153 and HIV Nup153 is furthermore a target for viruses to enable

their replication. Thereby viruses utilize different

strategies to take advantage of Nup153's central

function in nucleocytoplasmic transport.

Polioviruses or rhinoviruses, for example, express a

proteinase enzyme that is causing the cleavage and

degradation of Nup153, Nup98 and Nup62, which

consequently inhibits nucleocytoplasmic transport

(Belov et al., 2000) and increases the permeability

of the NPC. This increased permeability promotes

passive diffusion and the re-localization of host cell

nuclear proteins that take part in viral replication

(Meerovitch et al., 1993; McBride et al., 1996;

Gustin and Sarnow, 2001; Gustin and Sarnow,

2002; Park at al., 2008; Fitzgerald et al., 2013).

Inhibition of nucleocytoplasmic transport might

reduce the export of host mRNAs to the cytoplasm,

which in turn is reducing the competition for the

translation machinery and which is promoting viral

protein synthesis.

Other viruses, such as human immunodeficiency

virus 1 (HIV-1), need to enter the nucleus for their

replication, and therefore to pass through the NPC.

It is accepted that the HIV-1 nuclear import is an

active and energy-dependent process (Suzuki and

Craigie, 2007), which requires the help of import

receptors (Konig et al., 2008). Numerous nuclear

transport factors were identified that are implicated

in HIV-1 replication (Brass et al., 2008; Konig et

al., 2008) and among the best characterized are

Nup153 and Nup358. Both nucleoporins are

required for HIV-1 nuclear entry as their depletion

decreases HIV-1 integration into the host genome

(Konig et al., 2008; Di Nunzio et al., 2012).

Nup153 and Nup358 can interact with the HIV-1

capsid (Schaller et al., 2011; Di Nunzio et al.,

2013b; Matreyek et al., 2013) and Nup358 may

serve as a docking site for the HIV-1 pre-

integration complex (PIC) at the nuclear pore, while

Nup153 might play a role in the nuclear entry of the

PIC (Lee et al., 2010; Matreyek and Engelman,

2011). Nup153 may interact with PICs docked on

Nup358 and facilitate their transport through the

NPC. Nup153 depletion does not only decrease

HIV-1 nuclear entry, but also reduces the number of

HIV-1 integration sites into transcriptionally active

regions (Koh et al., 2013; Di Nunzio et al., 2013). It

has been proposed that Nup153 is directly guiding

the PIC to the genomic integration regions.

Besides the interaction with the PIC, Nup153 also

interacts with HIV-1 integrase in vitro when both

proteins are produced in recombinantly in bacteria

(Woodward et al., 2009), but this interaction was

not detected when both proteins were co-expressed

in mammalian cells (Di Nunzio et al., 2013),

suggesting that the HIV-1 capsid is the viral

determinant for the requirement of Nup153 and that

this interaction is critical for HIV-1 nuclear import

(Matreyek and Engelman, 2011; Di Nunzio et al.,

2013). Future investigations are required to further

support this notion.

9. Conclusion Progress in imaging techniques in recent years, both

on the light and electron microscopic level, in

combination with X-ray crystallography has

provided novel insights into the overall structure of

the NPC as well as into the organization and

localization of individual nucleoporins within the

NPC architecture.

While the structural roles of nucleoporins and their

functions in nucleocytoplasmic transport have been

appreciated for a long time, new functions for

nucleoporins - direct and indirect - are regularly

discovered.

The more we learn about this multifunctional usage

of nucleoporins it becomes apparent that they are

central for many cellular functions and processes,

both in interphase and mitosis.

Many of these processes, such as the regulation of

gene expression, have direct relevance for human

health and dysfunction of nucleoporins is not

surprisingly frequently associated with human

malignancies and viral infections.

How defects in nucleoporins alter cellular pathways

precisely and how this leads to a particular disease,

however, has remained largely elusive. Future

investigations in this context are urgently needed.

Acknowledgements This work was supported by grants from the Fonds

de la Recherche Scientifique-FNRS Belgium

(grants T.0237.13, 1.5019.12, and F.6006.10), the

Fonds Brachet and the Fonds Van Buuren.

References Panté N, Bastos R, McMorrow I, Burke B, Aebi U. Interactions and three-dimensional localization of a group of nuclear pore complex proteins. J Cell Biol. 1994 Aug;126(3):603-17

Paine PL, Moore LC, Horowitz SB. Nuclear envelope permeability. Nature. 1975 Mar 13;254(5496):109-14

De Robertis EM, Longthorne RF, Gurdon JB. Intracellular migration of nuclear proteins in Xenopus oocytes. Nature. 1978 Mar 16;272(5650):254-6

Park M, Dean M, Cooper CS, Schmidt M, O'Brien SJ, Blair DG, Vande Woude GF. Mechanism of met oncogene



activation. Cell. 1986 Jun 20;45(6):895-904

Peters R. Fluorescence microphotolysis to measure nucleocytoplasmic transport and intracellular mobility. Biochim Biophys Acta. 1986 Dec 22;864(3-4):305-59

Schulz B, Peters R. Nucleocytoplasmic protein traffic in single mammalian cells studied by fluorescence microphotolysis. Biochim Biophys Acta. 1987 Oct 1;930(3):419-31

King HW, Tempest PR, Merrifield KR, Rance AJ. tpr homologues activate met and raf. Oncogene. 1988 Jun;2(6):617-9

Peters R, Sauer H, Tschopp J, Fritzsch G. Transients of perforin pore formation observed by fluorescence microscopic single channel recording. EMBO J. 1990 Aug;9(8):2447-51

Finlay DR, Meier E, Bradley P, Horecka J, Forbes DJ. A complex of nuclear pore proteins required for pore function. J Cell Biol. 1991 Jul;114(1):169-83

Goldberg MW, Allen TD. High resolution scanning electron microscopy of the nuclear envelope: demonstration of a new, regular, fibrous lattice attached to the baskets of the nucleoplasmic face of the nuclear pores. J Cell Biol. 1992 Dec;119(6):1429-40

Greco A, Pierotti MA, Bongarzone I, Pagliardini S, Lanzi C, Della Porta G. TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas. Oncogene. 1992 Feb;7(2):237-42

Hinshaw JE, Carragher BO, Milligan RA. Architecture and design of the nuclear pore complex. Cell. 1992 Jun 26;69(7):1133-41

von Lindern M, Fornerod M, Soekarman N, van Baal S, Jaegle M, Hagemeijer A, Bootsma D, Grosveld G. Translocation t(6;9) in acute non-lymphocytic leukaemia results in the formation of a DEK-CAN fusion gene. Baillieres Clin Haematol. 1992 Oct;5(4):857-79

von Lindern M, van Baal S, Wiegant J, Raap A, Hagemeijer A, Grosveld G. Can, a putative oncogene associated with myeloid leukemogenesis, may be activated by fusion of its 3' half to different genes: characterization of the set gene. Mol Cell Biol. 1992 Aug;12(8):3346-55

Akey CW, Radermacher M. Architecture of the Xenopus nuclear pore complex revealed by three-dimensional cryo-electron microscopy. J Cell Biol. 1993 Jul;122(1):1-19

Cordes VC, Reidenbach S, Köhler A, Stuurman N, van Driel R, Franke WW. Intranuclear filaments containing a nuclear pore complex protein. J Cell Biol. 1993 Dec;123(6 Pt 1):1333-44

Grandi P, Doye V, Hurt EC. Purification of NSP1 reveals complex formation with 'GLFG' nucleoporins and a novel nuclear pore protein NIC96. EMBO J. 1993 Aug;12(8):3061-71

Grandi P, Doye V, Hurt EC. Purification of NSP1 reveals complex formation with 'GLFG' nucleoporins and a novel nuclear pore protein NIC96. EMBO J. 1993 Aug;12(8):3061-71

Meerovitch K, Svitkin YV, Lee HS, Lejbkowicz F, Kenan DJ, Chan EK, Agol VI, Keene JD, Sonenberg N. La autoantigen enhances and corrects aberrant translation of poliovirus RNA in reticulocyte lysate. J Virol. 1993 Jul;67(7):3798-807

Melchior F, Paschal B, Evans J, Gerace L. Inhibition of nuclear protein import by nonhydrolyzable analogues of GTP and identification of the small GTPase Ran/TC4 as

an essential transport factor. J Cell Biol. 1993 Dec;123(6 Pt 2):1649-59

Moore MS, Blobel G. The GTP-binding protein Ran/TC4 is required for protein import into the nucleus. Nature. 1993 Oct 14;365(6447):661-3

Sukegawa J, Blobel G. A nuclear pore complex protein that contains zinc finger motifs, binds DNA, and faces the nucleoplasm. Cell. 1993 Jan 15;72(1):29-38

Wente SR, Blobel G. A temperature-sensitive NUP116 null mutant forms a nuclear envelope seal over the yeast nuclear pore complex thereby blocking nucleocytoplasmic traffic. J Cell Biol. 1993 Oct;123(2):275-84

Rout MP, Wente SR. Pores for thought: nuclear pore complex proteins. Trends Cell Biol. 1994 Oct;4(10):357-65

Akey CW. Structural plasticity of the nuclear pore complex. J Mol Biol. 1995 Apr 28;248(2):273-93

Görlich D, Vogel F, Mills AD, Hartmann E, Laskey RA. Distinct functions for the two importin subunits in nuclear protein import. Nature. 1995 Sep 21;377(6546):246-8

Grandi P, Emig S, Weise C, Hucho F, Pohl T, Hurt EC. A novel nuclear pore protein Nup82p which specifically binds to a fraction of Nsp1p. J Cell Biol. 1995 Sep;130(6):1263-73

Grandi P, Schlaich N, Tekotte H, Hurt EC. Functional interaction of Nic96p with a core nucleoporin complex consisting of Nsp1p, Nup49p and a novel protein Nup57p. EMBO J. 1995 Jan 3;14(1):76-87

Guan T, Müller S, Klier G, Panté N, Blevitt JM, Haner M, Paschal B, Aebi U, Gerace L. Structural analysis of the p62 complex, an assembly of O-linked glycoproteins that localizes near the central gated channel of the nuclear pore complex. Mol Biol Cell. 1995 Nov;6(11):1591-603

Macaulay C, Meier E, Forbes DJ. Differential mitotic phosphorylation of proteins of the nuclear pore complex. J Biol Chem. 1995 Jan 6;270(1):254-62

Moroianu J, Blobel G. Protein export from the nucleus requires the GTPase Ran and GTP hydrolysis. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4318-22

Moroianu J, Blobel G, Radu A. Previously identified protein of uncertain function is karyopherin alpha and together with karyopherin beta docks import substrate at nuclear pore complexes. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2008-11

Moroianu J, Hijikata M, Blobel G, Radu A. Mammalian karyopherin alpha 1 beta and alpha 2 beta heterodimers: alpha 1 or alpha 2 subunit binds nuclear localization signal and beta subunit interacts with peptide repeat-containing nucleoporins. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6532-6

Paschal BM, Gerace L. Identification of NTF2, a cytosolic factor for nuclear import that interacts with nuclear pore complex protein p62. J Cell Biol. 1995 May;129(4):925-37

Radu A, Blobel G, Moore MS. Identification of a protein complex that is required for nuclear protein import and mediates docking of import substrate to distinct nucleoporins. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1769-73

Radu A, Moore MS, Blobel G. The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex. Cell. 1995 Apr 21;81(2):215-22

Rexach M, Blobel G. Protein import into nuclei: association and dissociation reactions involving transport substrate, transport factors, and nucleoporins. Cell. 1995 Dec



1;83(5):683-92

Soullam B, Worman HJ. Signals and structural features involved in integral membrane protein targeting to the inner nuclear membrane. J Cell Biol. 1995 Jul;130(1):15-27

Wen W, Meinkoth JL, Tsien RY, Taylor SS. Identification of a signal for rapid export of proteins from the nucleus. Cell. 1995 Aug 11;82(3):463-73

Bastos R, Lin A, Enarson M, Burke B. Targeting and function in mRNA export of nuclear pore complex protein Nup153. J Cell Biol. 1996 Sep;134(5):1141-56

Clarkson WD, Kent HM, Stewart M. Separate binding sites on nuclear transport factor 2 (NTF2) for GDP-Ran and the phenylalanine-rich repeat regions of nucleoporins p62 and Nsp1p. J Mol Biol. 1996 Nov 8;263(4):517-24

Görlich D, Panté N, Kutay U, Aebi U, Bischoff FR. Identification of different roles for RanGDP and RanGTP in nuclear protein import. EMBO J. 1996 Oct 15;15(20):5584-94

Hu T, Guan T, Gerace L. Molecular and functional characterization of the p62 complex, an assembly of nuclear pore complex glycoproteins. J Cell Biol. 1996 Aug;134(3):589-601

McBride AE, Schlegel A, Kirkegaard K. Human protein Sam68 relocalization and interaction with poliovirus RNA polymerase in infected cells. Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2296-301

Moroianu J, Blobel G, Radu A. The binding site of karyopherin alpha for karyopherin beta overlaps with a nuclear localization sequence. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6572-6

Siniossoglou S, Wimmer C, Rieger M, Doye V, Tekotte H, Weise C, Emig S, Segref A, Hurt EC. A novel complex of nucleoporins, which includes Sec13p and a Sec13p homolog, is essential for normal nuclear pores. Cell. 1996 Jan 26;84(2):265-75

Weis K, Dingwall C, Lamond AI. Characterization of the nuclear protein import mechanism using Ran mutants with altered nucleotide binding specificities. EMBO J. 1996 Dec 16;15(24):7120-8

Wesierska-Gadek J, Hohenuer H, Hitchman E, Penner E. Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis. Gastroenterology. 1996 Mar;110(3):840-7

Bastos R, Ribas de Pouplana L, Enarson M, Bodoor K, Burke B. Nup84, a novel nucleoporin that is associated with CAN/Nup214 on the cytoplasmic face of the nuclear pore complex. J Cell Biol. 1997 Jun 2;137(5):989-1000

Boche I, Fanning E. Nucleocytoplasmic recycling of the nuclear localization signal receptor alpha subunit in vivo is dependent on a nuclear export signal, energy, and RCC1. J Cell Biol. 1997 Oct 20;139(2):313-25

Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997 Sep 19;90(6):1051-60

Grandi P, Dang T, Pané N, Shevchenko A, Mann M, Forbes D, Hurt E. Nup93, a vertebrate homologue of yeast Nic96p, forms a complex with a novel 205-kDa protein and is required for correct nuclear pore assembly. Mol Biol Cell. 1997 Oct;8(10):2017-38

Iovine MK, Wente SR. A nuclear export signal in Kap95p is required for both recycling the import factor and interaction with the nucleoporin GLFG repeat regions of Nup116p and Nup100p. J Cell Biol. 1997 May 19;137(4):797-811

Izaurralde E, Kutay U, von Kobbe C, Mattaj IW, Görlich D.

The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus. EMBO J. 1997 Nov 3;16(21):6535-47

Kutay U, Bischoff FR, Kostka S, Kraft R, Görlich D. Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. Cell. 1997 Sep 19;90(6):1061-71

Kutay U, Izaurralde E, Bischoff FR, Mattaj IW, Görlich D. Dominant-negative mutants of importin-beta block multiple pathways of import and export through the nuclear pore complex. EMBO J. 1997 Mar 17;16(6):1153-63

Mahajan R, Delphin C, Guan T, Gerace L, Melchior F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell. 1997 Jan 10;88(1):97-107

Middeler G, Zerf K, Jenovai S, Thulig A, Tschödrich-Rotter M, Kubitscheck U, Peters R. The tumor suppressor p53 is subject to both nuclear import and export, and both are fast, energy-dependent and lectin-inhibited. Oncogene. 1997 Mar 27;14(12):1407-17

Moroianu J, Blobel G, Radu A. RanGTP-mediated nuclear export of karyopherin alpha involves its interaction with the nucleoporin Nup153. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9699-704

Schlaich NL, Häner M, Lustig A, Aebi U, Hurt EC. In vitro reconstitution of a heterotrimeric nucleoporin complex consisting of recombinant Nsp1p, Nup49p, and Nup57p. Mol Biol Cell. 1997 Jan;8(1):33-46

Yaseen NR, Blobel G. Cloning and characterization of human karyopherin beta3. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4451-6

Andrulis ED, Neiman AM, Zappulla DC, Sternglanz R. Perinuclear localization of chromatin facilitates transcriptional silencing. Nature. 1998 Aug 6;394(6693):592-5

Arts GJ, Fornerod M, Mattaj IW. Identification of a nuclear export receptor for tRNA. Curr Biol. 1998 Mar 12;8(6):305-14

Bailer SM, Siniossoglou S, Podtelejnikov A, Hellwig A, Mann M, Hurt E. Nup116p and nup100p are interchangeable through a conserved motif which constitutes a docking site for the mRNA transport factor gle2p. EMBO J. 1998 Feb 16;17(4):1107-19

Belgareh N, Snay-Hodge C, Pasteau F, Dagher S, Cole CN, Doye V. Functional characterization of a Nup159p-containing nuclear pore subcomplex. Mol Biol Cell. 1998 Dec;9(12):3475-92

Conti E, Uy M, Leighton L, Blobel G, Kuriyan J. Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha. Cell. 1998 Jul 24;94(2):193-204

Enarson P, Enarson M, Bastos R, Burke B. Amino-terminal sequences that direct nucleoporin nup153 to the inner surface of the nuclear envelope. Chromosoma. 1998 Sep;107(4):228-36

Fahrenkrog B, Hurt EC, Aebi U, Panté N. Molecular architecture of the yeast nuclear pore complex: localization of Nsp1p subcomplexes. J Cell Biol. 1998 Nov 2;143(3):577-88

Kaffman A, Rank NM, O'Neill EM, Huang LS, O'Shea EK. The receptor Msn5 exports the phosphorylated transcription factor Pho4 out of the nucleus. Nature. 1998 Dec 3;396(6710):482-6

Kehlenbach RH, Dickmanns A, Gerace L. Nucleocytoplasmic shuttling factors including Ran and



CRM1 mediate nuclear export of NFAT In vitro. J Cell Biol. 1998 May 18;141(4):863-74

Kiseleva E, Goldberg MW, Allen TD, Akey CW. Active nuclear pore complexes in Chironomus: visualization of transporter configurations related to mRNP export. J Cell Sci. 1998 Jan;111 ( Pt 2):223-36

Kutay U, Lipowsky G, Izaurralde E, Bischoff FR, Schwarzmaier P, Hartmann E, Görlich D. Identification of a tRNA-specific nuclear export receptor. Mol Cell. 1998 Feb;1(3):359-69

Ribbeck K, Lipowsky G, Kent HM, Stewart M, Görlich D. NTF2 mediates nuclear import of Ran. EMBO J. 1998 Nov 16;17(22):6587-98

Shah S, Forbes DJ. Separate nuclear import pathways converge on the nucleoporin Nup153 and can be dissected with dominant-negative inhibitors. Curr Biol. 1998 Dec 17-31;8(25):1376-86

Shah S, Tugendreich S, Forbes D. Major binding sites for the nuclear import receptor are the internal nucleoporin Nup153 and the adjacent nuclear filament protein Tpr. J Cell Biol. 1998 Apr 6;141(1):31-49

Yang Q, Rout MP, Akey CW. Three-dimensional architecture of the isolated yeast nuclear pore complex: functional and evolutionary implications. Mol Cell. 1998 Jan;1(2):223-34

Bayliss R, Ribbeck K, Akin D, Kent HM, Feldherr CM, Görlich D, Stewart M. Interaction between NTF2 and xFxFG-containing nucleoporins is required to mediate nuclear import of RanGDP. J Mol Biol. 1999 Oct 29;293(3):579-93

Bodoor K, Shaikh S, Salina D, Raharjo WH, Bastos R, Lohka M, Burke B. Sequential recruitment of NPC proteins to the nuclear periphery at the end of mitosis. J Cell Sci. 1999 Jul;112 ( Pt 13):2253-64

Danker T, Schillers H, Storck J, Shahin V, Krämer B, Wilhelmi M, Oberleithner H. Nuclear hourglass technique: an approach that detects electrically open nuclear pores in Xenopus laevis oocyte. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13530-5

Feng W, Benko AL, Lee JH, Stanford DR, Hopper AK. Antagonistic effects of NES and NLS motifs determine S. cerevisiae Rna1p subcellular distribution. J Cell Sci. 1999 Feb;112 ( Pt 3):339-47

Görlich D, Kutay U. Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol. 1999;15:607-60

Gregorio GV, Choudhuri K, Ma Y, Vegnente A, Mieli-Vergani G, Vergani D. Mimicry between the hepatitis B virus DNA polymerase and the antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis B virus infection. J Immunol. 1999 Feb 1;162(3):1802-10

Keminer O, Peters R. Permeability of single nuclear pores. Biophys J. 1999 Jul;77(1):217-28

Kosova B, Panté N, Rollenhagen C, Hurt E. Nup192p is a conserved nucleoporin with a preferential location at the inner site of the nuclear membrane. J Biol Chem. 1999 Aug 6;274(32):22646-51

Matsuoka Y, Takagi M, Ban T, Miyazaki M, Yamamoto T, Kondo Y, Yoneda Y. Identification and characterization of nuclear pore subcomplexes in mitotic extract of human somatic cells. Biochem Biophys Res Commun. 1999 Jan 19;254(2):417-23

Nakielny S, Shaikh S, Burke B, Dreyfuss G. Nup153 is an M9-containing mobile nucleoporin with a novel Ran-

binding domain. EMBO J. 1999 Apr 1;18(7):1982-95

Regelink AG, Dahan D, Möller LV, Coulton JW, Eijk P, Van Ulsen P, Dankert J, Van Alphen L. Variation in the composition and pore function of major outer membrane pore protein P2 of Haemophilus influenzae from cystic fibrosis patients. Antimicrob Agents Chemother. 1999 Feb;43(2):226-32

Vetter IR, Nowak C, Nishimoto T, Kuhlmann J, Wittinghofer A. Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport. Nature. 1999 Mar 4;398(6722):39-46

Bachi A, Braun IC, Rodrigues JP, Panté N, Ribbeck K, von Kobbe C, Kutay U, Wilm M, Görlich D, Carmo-Fonseca M, Izaurralde E. The C-terminal domain of TAP interacts with the nuclear pore complex and promotes export of specific CTE-bearing RNA substrates. RNA. 2000 Jan;6(1):136-58

Bayliss R, Kent HM, Corbett AH, Stewart M. Crystallization and initial X-ray diffraction characterization of complexes of FxFG nucleoporin repeats with nuclear transport factors. J Struct Biol. 2000 Sep;131(3):240-7

Bayliss R, Littlewood T, Stewart M. Structural basis for the interaction between FxFG nucleoporin repeats and importin-beta in nuclear trafficking. Cell. 2000 Jul 7;102(1):99-108

Belov GA, Evstafieva AG, Rubtsov YP, Mikitas OV, Vartapetian AB, Agol VI. Early alteration of nucleocytoplasmic traffic induced by some RNA viruses. Virology. 2000 Sep 30;275(2):244-8

Chaillan-Huntington C, Braslavsky CV, Kuhlmann J, Stewart M. Dissecting the interactions between NTF2, RanGDP, and the nucleoporin XFXFG repeats. J Biol Chem. 2000 Feb 25;275(8):5874-9

Guan T, Kehlenbach RH, Schirmer EC, Kehlenbach A, Fan F, Clurman BE, Arnheim N, Gerace L. Nup50, a nucleoplasmically oriented nucleoporin with a role in nuclear protein export. Mol Cell Biol. 2000 Aug;20(15):5619-30

Häcker G. The morphology of apoptosis. Cell Tissue Res. 2000 Jul;301(1):5-17

Haraguchi T, Koujin T, Hayakawa T, Kaneda T, Tsutsumi C, Imamoto N, Akazawa C, Sukegawa J, Yoneda Y, Hiraoka Y. Live fluorescence imaging reveals early recruitment of emerin, LBR, RanBP2, and Nup153 to reforming functional nuclear envelopes. J Cell Sci. 2000 Mar;113 ( Pt 5):779-94

Ho AK, Shen TX, Ryan KJ, Kiseleva E, Levy MA, Allen TD, Wente SR. Assembly and preferential localization of Nup116p on the cytoplasmic face of the nuclear pore complex by interaction with Nup82p. Mol Cell Biol. 2000 Aug;20(15):5736-48

Miller BR, Powers M, Park M, Fischer W, Forbes DJ. Identification of a new vertebrate nucleoporin, Nup188, with the use of a novel organelle trap assay. Mol Biol Cell. 2000 Oct;11(10):3381-96

Panté N, Thomas F, Aebi U, Burke B, Bastos R. Recombinant Nup153 incorporates in vivo into Xenopus oocyte nuclear pore complexes. J Struct Biol. 2000 Apr;129(2-3):306-12

Rout MP, Aitchison JD, Suprapto A, Hjertaas K, Zhao Y, Chait BT. The yeast nuclear pore complex: composition, architecture, and transport mechanism. J Cell Biol. 2000 Feb 21;148(4):635-51

Shulga N, Mosammaparast N, Wozniak R, Goldfarb DS. Yeast nucleoporins involved in passive nuclear envelope



permeability. J Cell Biol. 2000 May 29;149(5):1027-38

Siniossoglou S, Lutzmann M, Santos-Rosa H, Leonard K, Mueller S, Aebi U, Hurt E. Structure and assembly of the Nup84p complex. J Cell Biol. 2000 Apr 3;149(1):41-54

Smitherman M, Lee K, Swanger J, Kapur R, Clurman BE. Characterization and targeted disruption of murine Nup50, a p27(Kip1)-interacting component of the nuclear pore complex. Mol Cell Biol. 2000 Aug;20(15):5631-42

Smythe C, Jenkins HE, Hutchison CJ. Incorporation of the nuclear pore basket protein nup153 into nuclear pore structures is dependent upon lamina assembly: evidence from cell-free extracts of Xenopus eggs. EMBO J. 2000 Aug 1;19(15):3918-31

Tullio-Pelet A, Salomon R, Hadj-Rabia S, Mugnier C, de Laet MH, Chaouachi B, Bakiri F, Brottier P, Cattolico L, Penet C, Bégeot M, Naville D, Nicolino M, Chaussain JL, Weissenbach J, Munnich A, Lyonnet S. Mutant WD-repeat protein in triple-A syndrome. Nat Genet. 2000 Nov;26(3):332-5

Allen NP, Huang L, Burlingame A, Rexach M. Proteomic analysis of nucleoporin interacting proteins. J Biol Chem. 2001 Aug 3;276(31):29268-74

Belgareh N, Rabut G, Baï SW, van Overbeek M, Beaudouin J, Daigle N, Zatsepina OV, Pasteau F, Labas V, Fromont-Racine M, Ellenberg J, Doye V. An evolutionarily conserved NPC subcomplex, which redistributes in part to kinetochores in mammalian cells. J Cell Biol. 2001 Sep 17;154(6):1147-60

Ben-Efraim I, Gerace L. Gradient of increasing affinity of importin beta for nucleoporins along the pathway of nuclear import. J Cell Biol. 2001 Jan 22;152(2):411-7

Daigle N, Beaudouin J, Hartnell L, Imreh G, Hallberg E, Lippincott-Schwartz J, Ellenberg J. Nuclear pore complexes form immobile networks and have a very low turnover in live mammalian cells. J Cell Biol. 2001 Jul 9;154(1):71-84

Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z. Intrinsically disordered protein. J Mol Graph Model. 2001;19(1):26-59

Ferrando-May E, Cordes V, Biller-Ckovric I, Mirkovic J, Görlich D, Nicotera P. Caspases mediate nucleoporin cleavage, but not early redistribution of nuclear transport factors and modulation of nuclear permeability in apoptosis. Cell Death Differ. 2001 May;8(5):495-505

Fribourg S, Braun IC, Izaurralde E, Conti E. Structural basis for the recognition of a nucleoporin FG repeat by the NTF2-like domain of the TAP/p15 mRNA nuclear export factor. Mol Cell. 2001 Sep;8(3):645-56

Gustin KE, Sarnow P. Effects of poliovirus infection on nucleo-cytoplasmic trafficking and nuclear pore complex composition. EMBO J. 2001 Jan 15;20(1-2):240-9

Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet. 2001 Feb 1;10(3):283-90

Harborth J, Elbashir SM, Bechert K, Tuschl T, Weber K. Identification of essential genes in cultured mammalian cells using small interfering RNAs. J Cell Sci. 2001 Dec;114(Pt 24):4557-65

Nesher G, Margalit R, Ashkenazi YJ. Anti-nuclear envelope antibodies: Clinical associations. Semin Arthritis Rheum. 2001 Apr;30(5):313-20

Quimby BB, Leung SW, Bayliss R, Harreman MT, Thirumala G, Stewart M, Corbett AH. Functional analysis of the hydrophobic patch on nuclear transport factor 2 involved in interactions with the nuclear pore in vivo. J Biol Chem. 2001 Oct 19;276(42):38820-9

Ribbeck K, Görlich D. Kinetic analysis of translocation through nuclear pore complexes. EMBO J. 2001 Mar 15;20(6):1320-30

Shahin V, Danker T, Enss K, Ossig R, Oberleithner H. Evidence for Ca2+- and ATP-sensitive peripheral channels in nuclear pore complexes. FASEB J. 2001 Sep;15(11):1895-901

Vasu S, Shah S, Orjalo A, Park M, Fischer WH, Forbes DJ. Novel vertebrate nucleoporins Nup133 and Nup160 play a role in mRNA export. J Cell Biol. 2001 Oct 29;155(3):339-54

Vasu SK, Forbes DJ. Nuclear pores and nuclear assembly. Curr Opin Cell Biol. 2001 Jun;13(3):363-75

Walther TC, Fornerod M, Pickersgill H, Goldberg M, Allen TD, Mattaj IW. The nucleoporin Nup153 is required for nuclear pore basket formation, nuclear pore complex anchoring and import of a subset of nuclear proteins. EMBO J. 2001 Oct 15;20(20):5703-14

Allen NP, Patel SS, Huang L, Chalkley RJ, Burlingame A, Lutzmann M, Hurt EC, Rexach M. Deciphering networks of protein interactions at the nuclear pore complex. Mol Cell Proteomics. 2002 Dec;1(12):930-46

Bayliss R, Leung SW, Baker RP, Quimby BB, Corbett AH, Stewart M. Structural basis for the interaction between NTF2 and nucleoporin FxFG repeats. EMBO J. 2002 Jun 17;21(12):2843-53

Bayliss R, Littlewood T, Strawn LA, Wente SR, Stewart M. GLFG and FxFG nucleoporins bind to overlapping sites on importin-beta. J Biol Chem. 2002 Dec 27;277(52):50597-606

Brownawell AM, Macara IG. Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins. J Cell Biol. 2002 Jan 7;156(1):53-64

Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ. Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol. 2002 Sep 2;158(5):915-27

Denning DP, Uversky V, Patel SS, Fink AL, Rexach M. The Saccharomyces cerevisiae nucleoporin Nup2p is a natively unfolded protein. J Biol Chem. 2002 Sep 6;277(36):33447-55

Fahrenkrog B, Maco B, Fager AM, Köser J, Sauder U, Ullman KS, Aebi U. Domain-specific antibodies reveal multiple-site topology of Nup153 within the nuclear pore complex. J Struct Biol. 2002 Oct-Dec;140(1-3):254-67

Frosst P, Guan T, Subauste C, Hahn K, Gerace L. Tpr is localized within the nuclear basket of the pore complex and has a role in nuclear protein export. J Cell Biol. 2002 Feb 18;156(4):617-30

Gilchrist D, Mykytka B, Rexach M. Accelerating the rate of disassembly of karyopherin.cargo complexes. J Biol Chem. 2002 May 17;277(20):18161-72

Gould VE, Orucevic A, Zentgraf H, Gattuso P, Martinez N, Alonso A. Nup88 (karyoporin) in human malignant neoplasms and dysplasias: correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis. Hum Pathol. 2002 May;33(5):536-44

Gustin KE, Sarnow P. Inhibition of nuclear import and alteration of nuclear pore complex composition by rhinovirus. J Virol. 2002 Sep;76(17):8787-96



Hang J, Dasso M. Association of the human SUMO-1 protease SENP2 with the nuclear pore. J Biol Chem. 2002 May 31;277(22):19961-6

Kuersten S, Arts GJ, Walther TC, Englmeier L, Mattaj IW. Steady-state nuclear localization of exportin-t involves RanGTP binding and two distinct nuclear pore complex interaction domains. Mol Cell Biol. 2002 Aug;22(16):5708-20

Lutzmann M, Kunze R, Buerer A, Aebi U, Hurt E. Modular self-assembly of a Y-shaped multiprotein complex from seven nucleoporins. EMBO J. 2002 Feb 1;21(3):387-97

Panté N, Kann M. Nuclear pore complex is able to transport macromolecules with diameters of about 39 nm. Mol Biol Cell. 2002 Feb;13(2):425-34

Ribbeck K, Görlich D. The permeability barrier of nuclear pore complexes appears to operate via hydrophobic exclusion. EMBO J. 2002 Jun 3;21(11):2664-71

Walther TC, Pickersgill HS, Cordes VC, Goldberg MW, Allen TD, Mattaj IW, Fornerod M. The cytoplasmic filaments of the nuclear pore complex are dispensable for selective nuclear protein import. J Cell Biol. 2002 Jul 8;158(1):63-77

Wang B, Matsuoka S, Carpenter PB, Elledge SJ. 53BP1, a mediator of the DNA damage checkpoint. Science. 2002 Nov 15;298(5597):1435-8

Xu L, Kang Y, Cöl S, Massagué J. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus. Mol Cell. 2002 Aug;10(2):271-82

Zhang H, Saitoh H, Matunis MJ. Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex. Mol Cell Biol. 2002 Sep;22(18):6498-508

Boehmer T, Enninga J, Dales S, Blobel G, Zhong H. Depletion of a single nucleoporin, Nup107, prevents the assembly of a subset of nucleoporins into the nuclear pore complex. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):981-5

Cronshaw JM, Matunis MJ. The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5823-7

Denning DP, Patel SS, Uversky V, Fink AL, Rexach M. Disorder in the nuclear pore complex: the FG repeat regions of nucleoporins are natively unfolded. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2450-5

Emterling A, Skoglund J, Arbman G, Schneider J, Evertsson S, Carstensen J, Zhang H, Sun XF. Clinicopathological significance of Nup88 expression in patients with colorectal cancer. Oncology. 2003;64(4):361-9

Fahrenkrog B, Aebi U. The nuclear pore complex: nucleocytoplasmic transport and beyond. Nat Rev Mol Cell Biol. 2003 Oct;4(10):757-66

Galy V, Mattaj IW, Askjaer P. Caenorhabditis elegans nucleoporins Nup93 and Nup205 determine the limit of nuclear pore complex size exclusion in vivo. Mol Biol Cell. 2003 Dec;14(12):5104-15

Griffis ER, Xu S, Powers MA. Nup98 localizes to both nuclear and cytoplasmic sides of the nuclear pore and binds to two distinct nucleoporin subcomplexes. Mol Biol Cell. 2003 Feb;14(2):600-10

Harel A, Orjalo AV, Vincent T, Lachish-Zalait A, Vasu S, Shah S, Zimmerman E, Elbaum M, Forbes DJ. Removal of a single pore subcomplex results in vertebrate nuclei devoid of nuclear pores. Mol Cell. 2003 Apr;11(4):853-64

Hase ME, Cordes VC. Direct interaction with nup153 mediates binding of Tpr to the periphery of the nuclear pore complex. Mol Biol Cell. 2003 May;14(5):1923-40

Liu J, Prunuske AJ, Fager AM, Ullman KS. The COPI complex functions in nuclear envelope breakdown and is recruited by the nucleoporin Nup153. Dev Cell. 2003 Sep;5(3):487-98

Ma Z, Hill DA, Collins MH, Morris SW, Sumegi J, Zhou M, Zuppan C, Bridge JA. Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor. Genes Chromosomes Cancer. 2003 May;37(1):98-105

Pyhtila B, Rexach M. A gradient of affinity for the karyopherin Kap95p along the yeast nuclear pore complex. J Biol Chem. 2003 Oct 24;278(43):42699-709

Rout MP, Aitchison JD, Magnasco MO, Chait BT. Virtual gating and nuclear transport: the hole picture. Trends Cell Biol. 2003 Dec;13(12):622-8

Stoffler D, Feja B, Fahrenkrog B, Walz J, Typke D, Aebi U. Cryo-electron tomography provides novel insights into nuclear pore architecture: implications for nucleocytoplasmic transport. J Mol Biol. 2003 Apr 18;328(1):119-30

Suntharalingam M, Wente SR. Peering through the pore: nuclear pore complex structure, assembly, and function. Dev Cell. 2003 Jun;4(6):775-89

Walther TC, Alves A, Pickersgill H, Loïodice I, Hetzer M, Galy V, Hülsmann BB, Köcher T, Wilm M, Allen T, Mattaj IW, Doye V. The conserved Nup107-160 complex is critical for nuclear pore complex assembly. Cell. 2003 Apr 18;113(2):195-206

Bailey D, O'Hare P. Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1. J Biol Chem. 2004 Jan 2;279(1):692-703

Ball JR, Dimaano C, Ullman KS. The RNA binding domain within the nucleoporin Nup153 associates preferentially with single-stranded RNA. RNA. 2004 Jan;10(1):19-27

Beck M, Förster F, Ecke M, Plitzko JM, Melchior F, Gerisch G, Baumeister W, Medalia O. Nuclear pore complex structure and dynamics revealed by cryoelectron tomography. Science. 2004 Nov 19;306(5700):1387-90

Bernad R, van der Velde H, Fornerod M, Pickersgill H. Nup358/RanBP2 attaches to the nuclear pore complex via association with Nup88 and Nup214/CAN and plays a supporting role in CRM1-mediated nuclear protein export. Mol Cell Biol. 2004 Mar;24(6):2373-84

Cronshaw JM, Matunis MJ. The nuclear pore complex: disease associations and functional correlations. Trends Endocrinol Metab. 2004 Jan-Feb;15(1):34-9

Cushman I, Bowman BR, Sowa ME, Lichtarge O, Quiocho FA, Moore MS. Computational and biochemical identification of a nuclear pore complex binding site on the nuclear transport carrier NTF2. J Mol Biol. 2004 Nov 19;344(2):303-10

Enarson P, Rattner JB, Ou Y, Miyachi K, Horigome T, Fritzler MJ. Autoantigens of the nuclear pore complex. J Mol Med (Berl). 2004 Jul;82(7):423-33

Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R, Collins FS. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8963-8

Graux C, Cools J, Melotte C, Quentmeier H, Ferrando A,



Levine R, Vermeesch JR, Stul M, Dutta B, Boeckx N, Bosly A, Heimann P, Uyttebroeck A, Mentens N, Somers R, MacLeod RA, Drexler HG, Look AT, Gilliland DG, Michaux L, Vandenberghe P, Wlodarska I, Marynen P, Hagemeijer A. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet. 2004 Oct;36(10):1084-9

Griffis ER, Craige B, Dimaano C, Ullman KS, Powers MA. Distinct functional domains within nucleoporins Nup153 and Nup98 mediate transcription-dependent mobility. Mol Biol Cell. 2004 Apr;15(4):1991-2002

Kiseleva E, Allen TD, Rutherford S, Bucci M, Wente SR, Goldberg MW. Yeast nuclear pore complexes have a cytoplasmic ring and internal filaments. J Struct Biol. 2004 Mar;145(3):272-88

Krull S, Thyberg J, Björkroth B, Rackwitz HR, Cordes VC. Nucleoporins as components of the nuclear pore complex core structure and Tpr as the architectural element of the nuclear basket. Mol Biol Cell. 2004 Sep;15(9):4261-77

Ohba T, Schirmer EC, Nishimoto T, Gerace L. Energy- and temperature-dependent transport of integral proteins to the inner nuclear membrane via the nuclear pore. J Cell Biol. 2004 Dec 20;167(6):1051-62

Rabut G, Doye V, Ellenberg J. Mapping the dynamic organization of the nuclear pore complex inside single living cells. Nat Cell Biol. 2004 Nov;6(11):1114-21

Rabut G, Lénárt P, Ellenberg J. Dynamics of nuclear pore complex organization through the cell cycle. Curr Opin Cell Biol. 2004 Jun;16(3):314-21

Strawn LA, Shen T, Shulga N, Goldfarb DS, Wente SR. Minimal nuclear pore complexes define FG repeat domains essential for transport. Nat Cell Biol. 2004 Mar;6(3):197-206

Yang W, Gelles J, Musser SM. Imaging of single-molecule translocation through nuclear pore complexes. Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):12887-92

Zeitler B, Weis K. The FG-repeat asymmetry of the nuclear pore complex is dispensable for bulk nucleocytoplasmic transport in vivo. J Cell Biol. 2004 Nov 22;167(4):583-90

Antonin W, Franz C, Haselmann U, Antony C, Mattaj IW. The integral membrane nucleoporin pom121 functionally links nuclear pore complex assembly and nuclear envelope formation. Mol Cell. 2005 Jan 7;17(1):83-92

Ball JR, Ullman KS. Versatility at the nuclear pore complex: lessons learned from the nucleoporin Nup153. Chromosoma. 2005 Nov;114(5):319-30

Hawryluk-Gara LA, Shibuya EK, Wozniak RW. Vertebrate Nup53 interacts with the nuclear lamina and is required for the assembly of a Nup93-containing complex. Mol Biol Cell. 2005 May;16(5):2382-94

Kubitscheck U, Grünwald D, Hoekstra A, Rohleder D, Kues T, Siebrasse JP, Peters R. Nuclear transport of single molecules: dwell times at the nuclear pore complex. J Cell Biol. 2005 Jan 17;168(2):233-43

Liu SM, Stewart M. Structural basis for the high-affinity binding of nucleoporin Nup1p to the Saccharomyces cerevisiae importin-beta homologue, Kap95p. J Mol Biol. 2005 Jun 10;349(3):515-25

Lutzmann M, Kunze R, Stangl K, Stelter P, Tóth KF, Böttcher B, Hurt E. Reconstitution of Nup157 and Nup145N into the Nup84 complex. J Biol Chem. 2005 May 6;280(18):18442-51

Nybakken K, Vokes SA, Lin TY, McMahon AP, Perrimon N. A genome-wide RNA interference screen in Drosophila

melanogaster cells for new components of the Hh signaling pathway. Nat Genet. 2005 Dec;37(12):1323-32

Paulillo SM, Phillips EM, Köser J, Sauder U, Ullman KS, Powers MA, Fahrenkrog B. Nucleoporin domain topology is linked to the transport status of the nuclear pore complex. J Mol Biol. 2005 Aug 26;351(4):784-98

Peters R. Translocation through the nuclear pore complex: selectivity and speed by reduction-of-dimensionality. Traffic. 2005 May;6(5):421-7

Reverter D, Lima CD. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. Nature. 2005 Jun 2;435(7042):687-92

Schwartz TU. Modularity within the architecture of the nuclear pore complex. Curr Opin Struct Biol. 2005 Apr;15(2):221-6

Soop T, Ivarsson B, Björkroth B, Fomproix N, Masich S, Cordes VC, Daneholt B. Nup153 affects entry of messenger and ribosomal ribonucleoproteins into the nuclear basket during export. Mol Biol Cell. 2005 Dec;16(12):5610-20

Zhong H, Takeda A, Nazari R, Shio H, Blobel G, Yaseen NR. Carrier-independent nuclear import of the transcription factor PU.1 via RanGTP-stimulated binding to Nup153. J Biol Chem. 2005 Mar 18;280(11):10675-82

Basel-Vanagaite L, Muncher L, Straussberg R, Pasmanik-Chor M, Yahav M, Rainshtein L, Walsh CA, Magal N, Taub E, Drasinover V, Shalev H, Attia R, Rechavi G, Simon AJ, Shohat M. Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann Neurol. 2006 Aug;60(2):214-22

Devos D, Dokudovskaya S, Williams R, Alber F, Eswar N, Chait BT, Rout MP, Sali A. Simple fold composition and modular architecture of the nuclear pore complex. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2172-7

Frey S, Richter RP, Görlich D. FG-rich repeats of nuclear pore proteins form a three-dimensional meshwork with hydrogel-like properties. Science. 2006 Nov 3;314(5800):815-7

Hübner S, Eam JE, Hübner A, Jans DA. Laminopathy-inducing lamin A mutants can induce redistribution of lamin binding proteins into nuclear aggregates. Exp Cell Res. 2006 Jan 15;312(2):171-83

Lim RY, Aebi U, Stoffler D. From the trap to the basket: getting to the bottom of the nuclear pore complex. Chromosoma. 2006 Feb;115(1):15-26

Lim RY, Fahrenkrog B. The nuclear pore complex up close. Curr Opin Cell Biol. 2006 Jun;18(3):342-7

Lim RY, Huang NP, Köser J, Deng J, Lau KH, Schwarz-Herion K, Fahrenkrog B, Aebi U. Flexible phenylalanine-glycine nucleoporins as entropic barriers to nucleocytoplasmic transport. Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9512-7

Mansfeld J, Güttinger S, Hawryluk-Gara LA, Panté N, Mall M, Galy V, Haselmann U, Mühlhäusser P, Wozniak RW, Mattaj IW, Kutay U, Antonin W. The conserved transmembrane nucleoporin NDC1 is required for nuclear pore complex assembly in vertebrate cells. Mol Cell. 2006 Apr 7;22(1):93-103

Mendjan S, Taipale M, Kind J, Holz H, Gebhardt P, Schelder M, Vermeulen M, Buscaino A, Duncan K, Mueller J, Wilm M, Stunnenberg HG, Saumweber H, Akhtar A. Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. Mol Cell. 2006 Mar 17;21(6):811-23



Orlic M, Spencer CE, Wang L, Gallie BL. Expression analysis of 6p22 genomic gain in retinoblastoma. Genes Chromosomes Cancer. 2006 Jan;45(1):72-82

Paulillo SM, Powers MA, Ullman KS, Fahrenkrog B. Changes in nucleoporin domain topology in response to chemical effectors. J Mol Biol. 2006 Oct 13;363(1):39-50

Prunuske AJ, Liu J, Elgort S, Joseph J, Dasso M, Ullman KS. Nuclear envelope breakdown is coordinated by both Nup358/RanBP2 and Nup153, two nucleoporins with zinc finger modules. Mol Biol Cell. 2006 Feb;17(2):760-9

Rasala BA, Orjalo AV, Shen Z, Briggs S, Forbes DJ. ELYS is a dual nucleoporin/kinetochore protein required for nuclear pore assembly and proper cell division. Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17801-6

Alber F, Dokudovskaya S, Veenhoff LM, Zhang W, Kipper J, Devos D, Suprapto A, Karni-Schmidt O, Williams R, Chait BT, Rout MP, Sali A. Determining the architectures of macromolecular assemblies. Nature. 2007 Nov 29;450(7170):683-94

Alber F, Dokudovskaya S, Veenhoff LM, Zhang W, Kipper J, Devos D, Suprapto A, Karni-Schmidt O, Williams R, Chait BT, Sali A, Rout MP. The molecular architecture of the nuclear pore complex. Nature. 2007 Nov 29;450(7170):695-701

Beck M, Lucić V, Förster F, Baumeister W, Medalia O. Snapshots of nuclear pore complexes in action captured by cryo-electron tomography. Nature. 2007 Oct 4;449(7162):611-5

Brown CR, Silver PA. Transcriptional regulation at the nuclear pore complex. Curr Opin Genet Dev. 2007 Apr;17(2):100-6

Denning DP, Rexach MF. Rapid evolution exposes the boundaries of domain structure and function in natively unfolded FG nucleoporins. Mol Cell Proteomics. 2007 Feb;6(2):272-82

Frey S, Görlich D. A saturated FG-repeat hydrogel can reproduce the permeability properties of nuclear pore complexes. Cell. 2007 Aug 10;130(3):512-23

Higa MM, Alam SL, Sundquist WI, Ullman KS. Molecular characterization of the Ran-binding zinc finger domain of Nup153. J Biol Chem. 2007 Jun 8;282(23):17090-100

Lim RY, Fahrenkrog B, Köser J, Schwarz-Herion K, Deng J, Aebi U. Nanomechanical basis of selective gating by the nuclear pore complex. Science. 2007 Oct 26;318(5850):640-3

Patel SS, Belmont BJ, Sante JM, Rexach MF. Natively unfolded nucleoporins gate protein diffusion across the nuclear pore complex. Cell. 2007 Apr 6;129(1):83-96

Schwarz-Herion K, Maco B, Sauder U, Fahrenkrog B. Domain topology of the p62 complex within the 3-D architecture of the nuclear pore complex. J Mol Biol. 2007 Jul 20;370(4):796-806

Suzuki Y, Craigie R. The road to chromatin - nuclear entry of retroviruses. Nat Rev Microbiol. 2007 Mar;5(3):187-96

Worman HJ, Bonne G. "Laminopathies": a wide spectrum of human diseases. Exp Cell Res. 2007 Jun 10;313(10):2121-33

Beck M, Medalia O. Structural and functional insights into nucleocytoplasmic transport. Histol Histopathol. 2008 Aug;23(8):1025-33

Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J, Elledge SJ. Identification of host proteins required for HIV infection through a functional genomic screen. Science. 2008 Feb 15;319(5865):921-6

Brohawn SG, Leksa NC, Spear ED, Rajashankar KR, Schwartz TU. Structural evidence for common ancestry of the nuclear pore complex and vesicle coats. Science. 2008 Nov 28;322(5906):1369-73

Dange T, Grünwald D, Grünwald A, Peters R, Kubitscheck U. Autonomy and robustness of translocation through the nuclear pore complex: a single-molecule study. J Cell Biol. 2008 Oct 6;183(1):77-86

Debler EW, Ma Y, Seo HS, Hsia KC, Noriega TR, Blobel G, Hoelz A. A fence-like coat for the nuclear pore membrane. Mol Cell. 2008 Dec 26;32(6):815-26

Dultz E, Zanin E, Wurzenberger C, Braun M, Rabut G, Sironi L, Ellenberg J. Systematic kinetic analysis of mitotic dis- and reassembly of the nuclear pore in living cells. J Cell Biol. 2008 Mar 10;180(5):857-65

Hawryluk-Gara LA, Platani M, Santarella R, Wozniak RW, Mattaj IW. Nup53 is required for nuclear envelope and nuclear pore complex assembly. Mol Biol Cell. 2008 Apr;19(4):1753-62

Heidenblad M, Lindgren D, Jonson T, Liedberg F, Veerla S, Chebil G, Gudjonsson S, Borg A, Månsson W, Höglund M. Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors. BMC Med Genomics. 2008 Jan 31;1:3

König R, Zhou Y, Elleder D, Diamond TL, Bonamy GM, Irelan JT, Chiang CY, Tu BP, De Jesus PD, Lilley CE, Seidel S, Opaluch AM, Caldwell JS, Weitzman MD, Kuhen KL, Bandyopadhyay S, Ideker T, Orth AP, Miraglia LJ, Bushman FD, Young JA, Chanda SK. Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell. 2008 Oct 3;135(1):49-60

Nousiainen HO, Kestilä M, Pakkasjärvi N, Honkala H, Kuure S, Tallila J, Vuopala K, Ignatius J, Herva R, Peltonen L. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet. 2008 Feb;40(2):155-7

Park N, Katikaneni P, Skern T, Gustin KE. Differential targeting of nuclear pore complex proteins in poliovirus-infected cells. J Virol. 2008 Feb;82(4):1647-55

Schrader N, Koerner C, Koessmeier K, Bangert JA, Wittinghofer A, Stoll R, Vetter IR. The crystal structure of the Ran-Nup153ZnF2 complex: a general Ran docking site at the nuclear pore complex. Structure. 2008 Jul;16(7):1116-25

Zhang X, Chen S, Yoo S, Chakrabarti S, Zhang T, Ke T, Oberti C, Yong SL, Fang F, Li L, de la Fuente R, Wang L, Chen Q, Wang QK. Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell. 2008 Dec 12;135(6):1017-27

Zhou H, Xu M, Huang Q, Gates AT, Zhang XD, Castle JC, Stec E, Ferrer M, Strulovici B, Hazuda DJ, Espeseth AS. Genome-scale RNAi screen for host factors required for HIV replication. Cell Host Microbe. 2008 Nov 13;4(5):495-504

Brohawn SG, Partridge JR, Whittle JR, Schwartz TU. The nuclear pore complex has entered the atomic age. Structure. 2009 Sep 9;17(9):1156-68

Brohawn SG, Schwartz TU. Molecular architecture of the Nup84-Nup145C-Sec13 edge element in the nuclear pore complex lattice. Nat Struct Mol Biol. 2009 Nov;16(11):1173-7

Brohawn SG, Schwartz TU. A lattice model of the nuclear pore complex. Commun Integr Biol. 2009 May;2(3):205-7

Busch A, Kiel T, Heupel WM, Wehnert M, Hübner S.



Nuclear protein import is reduced in cells expressing nuclear envelopathy-causing lamin A mutants. Exp Cell Res. 2009 Aug 15;315(14):2373-85

Fiserova J, Kiseleva E, Goldberg MW. Nuclear envelope and nuclear pore complex structure and organization in tobacco BY-2 cells. Plant J. 2009 Jul;59(2):243-55

Kampmann M, Blobel G. Three-dimensional structure and flexibility of a membrane-coating module of the nuclear pore complex. Nat Struct Mol Biol. 2009 Jul;16(7):782-8

Lim RY, Deng J. Interaction forces and reversible collapse of a polymer brush-gated nanopore. ACS Nano. 2009 Oct 27;3(10):2911-8

Lin SH, Liu CM, Liu YL, Shen-Jang Fann C, Hsiao PC, Wu JY, Hung SI, Chen CH, Wu HM, Jou YS, Liu SK, Hwang TJ, Hsieh MH, Chang CC, Yang WC, Lin JJ, Chou FH, Faraone SV, Tsuang MT, Hwu HG, Chen WJ. Clustering by neurocognition for fine mapping of the schizophrenia susceptibility loci on chromosome 6p. Genes Brain Behav. 2009 Nov;8(8):785-94

Lussi YC, Fahrenkrog B.. Nuclear pore complex organization and nucleoporin functions Nuclear transport, Landes Bioscience. 2009: 19-37.

Mackay DR, Elgort SW, Ullman KS.. The nucleoporin Nup153 has separable roles in both early mitotic progression and the resolution of mitosis. Mol Biol Cell. 2009 Mar;20(6):1652-60. doi: 10.1091/mbc.E08-08-0883. Epub 2009 Jan 21.

Nakahara J, Kanekura K, Nawa M, Aiso S, Suzuki N.. Abnormal expression of TIP30 and arrested nucleocytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis. J Clin Invest. 2009 Jan;119(1):169-81. doi: 10.1172/JCI35440. Epub 2008 Dec 22.

Onischenko E, Stanton LH, Madrid AS, Kieselbach T, Weis K.. Role of the Ndc1 interaction network in yeast nuclear pore complex assembly and maintenance. J Cell Biol. 2009 May 4;185(3):475-91. doi: 10.1083/jcb.200810030.

Partridge JR, Schwartz TU.. Crystallographic and biochemical analysis of the Ran-binding zinc finger domain. J Mol Biol. 2009 Aug 14;391(2):375-89. doi: 10.1016/j.jmb.2009.06.011. Epub 2009 Jun 6.

Peters R.. Translocation through the nuclear pore: Kaps pave the way. Bioessays. 2009 Apr;31(4):466-77. doi: 10.1002/bies.200800159.

Seo HS, Ma Y, Debler EW, Wacker D, Kutik S, Blobel G, Hoelz A.. Structural and functional analysis of Nup120 suggests ring formation of the Nup84 complex. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14281-6. doi: 10.1073/pnas.0907453106. Epub 2009 Aug 11.

Wang Y, Dasso M.. SUMOylation and deSUMOylation at a glance. J Cell Sci. 2009 Dec 1;122(Pt 23):4249-52. doi: 10.1242/jcs.050542. (REVIEW)

Woodward CL, Prakobwanakit S, Mosessian S, Chow SA.. Integrase interacts with nucleoporin NUP153 to mediate the nuclear import of human immunodeficiency virus type 1. J Virol. 2009 Jul;83(13):6522-33. doi: 10.1128/JVI.02061-08. Epub 2009 Apr 15.

Ader C, Frey S, Maas W, Schmidt HB, Gorlich D, Baldus M.. Amyloid-like interactions within nucleoporin FG hydrogels. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6281-5. doi: 10.1073/pnas.0910163107. Epub 2010 Mar 18.

Dolker N, Zachariae U, Grubmuller H.. Hydrophilic linkers and polar contacts affect aggregation of FG repeat peptides. Biophys J. 2010 Jun 2;98(11):2653-61. doi: 10.1016/j.bpj.2010.02.049.

Frenkiel-Krispin D, Maco B, Aebi U, Medalia O.. Structural analysis of a metazoan nuclear pore complex reveals a fused concentric ring architecture. J Mol Biol. 2010 Jan 22;395(3):578-86. doi: 10.1016/j.jmb.2009.11.010. Epub 2009 Nov 11.

Gorello P, La Starza R, Di Giacomo D, Messina M, Puzzolo MC, Crescenzi B, Santoro A, Chiaretti S, Mecucci C.. SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic leukemia. Haematologica. 2010 Dec;95(12):2161-3. doi: 10.3324/haematol.2010.029769. Epub 2010 Sep 17.

Krull S, Dorries J, Boysen B, Reidenbach S, Magnius L, Norder H, Thyberg J, Cordes VC.. Protein Tpr is required for establishing nuclear pore-associated zones of heterochromatin exclusion. EMBO J. 2010 May 19;29(10):1659-73. doi: 10.1038/emboj.2010.54. Epub 2010 Apr 20.

Lee K, Ambrose Z, Martin TD, Oztop I, Mulky A, Julias JG, Vandegraaff N, Baumann JG, Wang R, Yuen W, Takemura T, Shelton K, Taniuchi I, Li Y, Sodroski J, Littman DR, Coffin JM, Hughes SH, Unutmaz D, Engelman A, KewalRamani VN.. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe. 2010 Mar 18;7(3):221-33. doi: 10.1016/j.chom.2010.02.007.

Lussi YC, Shumaker DK, Shimi T, Fahrenkrog B.. The nucleoporin Nup153 affects spindle checkpoint activity due to an association with Mad1. Nucleus. 2010 Jan-Feb;1(1):71-84. doi: 10.4161/nucl.1.1.10244.

Mackay DR, Makise M, Ullman KS.. Defects in nuclear pore assembly lead to activation of an Aurora B-mediated abscission checkpoint. J Cell Biol. 2010 Nov 29;191(5):923-31. doi: 10.1083/jcb.201007124. Epub 2010 Nov 22.

Mitchell JM, Mansfeld J, Capitanio J, Kutay U, Wozniak RW.. Pom121 links two essential subcomplexes of the nuclear pore complex core to the membrane. J Cell Biol. 2010 Nov 1;191(3):505-21. doi: 10.1083/jcb.201007098. Epub 2010 Oct 25.

Neumann N, Lundin D, Poole AM.. Comparative genomic evidence for a complete nuclear pore complex in the last eukaryotic common ancestor. PLoS One. 2010 Oct 8;5(10):e13241. doi: 10.1371/journal.pone.0013241.

Tetenbaum-Novatt J, Rout MP.. The mechanism of nucleocytoplasmic transport through the nuclear pore complex. Cold Spring Harb Symp Quant Biol. 2010;75:567-84. doi: 10.1101/sqb.2010.75.033. Epub 2011 Mar 29.

Theerthagiri G, Eisenhardt N, Schwarz H, Antonin W.. The nucleoporin Nup188 controls passage of membrane proteins across the nuclear pore complex. J Cell Biol. 2010 Jun 28;189(7):1129-42. doi: 10.1083/jcb.200912045. Epub 2010 Jun 21.

Vaquerizas JM, Suyama R, Kind J, Miura K, Luscombe NM, Akhtar A.. Nuclear pore proteins nup153 and megator define transcriptionally active regions in the Drosophila genome. PLoS Genet. 2010 Feb 12;6(2):e1000846. doi: 10.1371/journal.pgen.1000846.

Wente SR, Rout MP.. The nuclear pore complex and nuclear transport. Cold Spring Harb Perspect Biol. 2010 Oct;2(10):a000562. doi: 10.1101/cshperspect.a000562. Epub 2010 Jul 14. (REVIEW)

Xu D, Farmer A, Chook YM.. Recognition of nuclear targeting signals by Karyopherin-beta proteins. Curr Opin Struct Biol. 2010 Dec;20(6):782-90. doi: 10.1016/j.sbi.2010.09.008. Epub 2010 Oct 13. (REVIEW)

Yamada J, Phillips JL, Patel S, Goldfien G, Calestagne-Morelli A, Huang H, Reza R, Acheson J, Krishnan VV,



Newsam S, Gopinathan A, Lau EY, Colvin ME, Uversky VN, Rexach MF.. A bimodal distribution of two distinct categories of intrinsically disordered structures with separate functions in FG nucleoporins. Mol Cell Proteomics. 2010 Oct;9(10):2205-24. doi: 10.1074/mcp.M000035-MCP201. Epub 2010 Apr 5.

Zhou L, Pante N.. The nucleoporin Nup153 maintains nuclear envelope architecture and is required for cell migration in tumor cells. FEBS Lett. 2010 Jul 16;584(14):3013-20. doi: 10.1016/j.febslet.2010.05.038. Epub 2010 May 24.

Al-Haboubi T, Shumaker DK, Koser J, Wehnert M, Fahrenkrog B.. Distinct association of the nuclear pore protein Nup153 with A- and B-type lamins. Nucleus. 2011 Sep-Oct;2(5):500-9. doi: http://dx.doi.org/10.4161/nucl.2.5.17913. Epub 2011 Sep 1.

Amlacher S, Sarges P, Flemming D, van Noort V, Kunze R, Devos DP, Arumugam M, Bork P, Hurt E.. Insight into structure and assembly of the nuclear pore complex by utilizing the genome of a eukaryotic thermophile. Cell. 2011 Jul 22;146(2):277-89. doi: 10.1016/j.cell.2011.06.039.

Ando Y, Tomaru Y, Morinaga A, Burroughs AM et al.. Nuclear pore complex protein mediated nuclear localization of dicer protein in human cells. PLoS One. 2011;6(8):e23385. doi: 10.1371/journal.pone.0023385. Epub 2011 Aug 15.

Gough SM, Slape CI, Aplan PD.. NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. Blood. 2011 Dec 8;118(24):6247-57. doi: 10.1182/blood-2011-07-328880. Epub 2011 Sep 26. (REVIEW)

Matreyek KA, Engelman A.. The requirement for nucleoporin NUP153 during human immunodeficiency virus type 1 infection is determined by the viral capsid. J Virol. 2011 Aug;85(15):7818-27. doi: 10.1128/JVI.00325-11. Epub 2011 May 18.

Milles S, Lemke EA.. Single molecule study of the intrinsically disordered FG-repeat nucleoporin 153. Biophys J. 2011 Oct 5;101(7):1710-9. doi: 10.1016/j.bpj.2011.08.025.

Moussavi-Baygi R, Jamali Y, Karimi R, Mofrad MR.. Brownian dynamics simulation of nucleocytoplasmic transport: a coarse-grained model for the functional state of the nuclear pore complex. PLoS Comput Biol. 2011 Jun;7(6):e1002049. doi: 10.1371/journal.pcbi.1002049. Epub 2011 Jun 2.

Schaller T, Ocwieja KE, Rasaiyaah J, Price AJ et al.. HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog. 2011 Dec;7(12):e1002439. doi: 10.1371/journal.ppat.1002439. Epub 2011 Dec 8.

Wan G, Mathur R, Hu X, Zhang X, Lu X.. miRNA response to DNA damage. Trends Biochem Sci. 2011 Sep;36(9):478-84. doi: 10.1016/j.tibs.2011.06.002. Epub 2011 Jul 7. (REVIEW)

Zhang X, Wan G, Berger FG, He X, Lu X.. The ATM kinase induces microRNA biogenesis in the DNA damage response. Mol Cell. 2011 Feb 18;41(4):371-83. doi: 10.1016/j.molcel.2011.01.020.

Aitchison JD, Rout MP.. The yeast nuclear pore complex and transport through it. Genetics. 2012 Mar;190(3):855-

83. doi: 10.1534/genetics.111.127803.

Chatel G, Fahrenkrog B.. Dynamics and diverse functions of nuclear pore complex proteins. Nucleus. 2012 Mar

1;3(2):162-71. doi: 10.4161/nucl.19674. Epub 2012 Mar 1. (REVIEW)

Chow KH, Elgort S, Dasso M, Ullman KS.. Two distinct sites in Nup153 mediate interaction with the SUMO proteases SENP1 and SENP2. Nucleus. 2012 Jul 1;3(4):349-58. Epub 2012 Jun 12.

D'Angelo MA, Gomez-Cavazos JS, Mei A, Lackner DH, Hetzer MW.. A change in nuclear pore complex composition regulates cell differentiation. Dev Cell. 2012 Feb 14;22(2):446-58. doi: 10.1016/j.devcel.2011.11.021. Epub 2012 Jan 19.

Datta S, Chowdhury A, Ghosh M, Das K, Jha P, Colah R, Mukerji M, Majumder PP.. A genome-wide search for non-UGT1A1 markers associated with unconjugated bilirubin level reveals significant association with a polymorphic marker near a gene of the nucleoporin family. Ann Hum Genet. 2012 Jan;76(1):33-41. doi: 10.1111/j.1469-1809.2011.00688.x. Epub 2011 Nov 28.

Di Nunzio F, Danckaert A, Fricke T, Perez P, Fernandez J, Perret E, Roux P, Shorte S, Charneau P, Diaz-Griffero F, Arhel NJ.. Human nucleoporins promote HIV-1 docking at the nuclear pore, nuclear import and integration. PLoS One. 2012;7(9):e46037. doi: 10.1371/journal.pone.0046037. Epub 2012 Sep 25.

Grossman E, Medalia O, Zwerger M.. Functional architecture of the nuclear pore complex. Annu Rev Biophys. 2012;41:557-84. doi: 10.1146/annurev-biophys-050511-102328. (REVIEW)

Hulsmann BB, Labokha AA, Gorlich D.. The permeability of reconstituted nuclear pores provides direct evidence for the selective phase model. Cell. 2012 Aug 17;150(4):738-51. doi: 10.1016/j.cell.2012.07.019.

Lara-Gonzalez P, Westhorpe FG, Taylor SS.. The spindle assembly checkpoint. Curr Biol. 2012 Nov 20;22(22):R966-80. doi: 10.1016/j.cub.2012.10.006. (REVIEW)

Lemaitre C, Fischer B, Kalousi A, Hoffbeck AS et al.. The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response. Oncogene. 2012 Nov 8;31(45):4803-9. doi: 10.1038/onc.2011.638. Epub 2012 Jan 16.

Maimon T, Elad N, Dahan I, Medalia O.. The human nuclear pore complex as revealed by cryo-electron tomography. Structure. 2012 Jun 6;20(6):998-1006. doi: 10.1016/j.str.2012.03.025. Epub 2012 May 24.

Makise M, Mackay DR, Elgort S, Shankaran SS, Adam SA, Ullman KS.. The Nup153-Nup50 protein interface and its role in nuclear import. J Biol Chem. 2012 Nov 9;287(46):38515-22. doi: 10.1074/jbc.M112.378893. Epub 2012 Sep 24.

Ogawa Y, Miyamoto Y, Oka M, Yoneda Y.. The interaction between importin-alpha and Nup153 promotes importin-alpha/beta-mediated nuclear import. Traffic. 2012 Jul;13(7):934-46. doi: 10.1111/j.1600-0854.2012.01367.x. Epub 2012 May 14.

Moudry P, Lukas C, Macurek L, Neumann B et al.. Nucleoporin NUP153 guards genome integrity by promoting nuclear import of 53BP1. Cell Death Differ. 2012 May;19(5):798-807. doi: 10.1038/cdd.2011.150. Epub 2011 Nov 11.

Sachdev R, Sieverding C, Flotenmeyer M, Antonin W.. The C-terminal domain of Nup93 is essential for assembly of the structural backbone of nuclear pore complexes. Mol Biol Cell. 2012 Feb;23(4):740-9. doi: 10.1091/mbc.E11-09-0761. Epub 2011 Dec 14.

Siebrasse JP, Kaminski T, Kubitscheck U.. Nuclear export of single native mRNA molecules observed by light sheet



fluorescence microscopy. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9426-31. doi: 10.1073/pnas.1201781109. Epub 2012 May 21.

Tarazon E, Rivera M, Rosello-Lleti E et al.. Heart failure induces significant changes in nuclear pore complex of human cardiomyocytes. PLoS One. 2012;7(11):e48957. doi: 10.1371/journal.pone.0048957. Epub 2012 Nov 12.

Tetenbaum-Novatt J, Hough LE, Mironska R, McKenney AS, Rout MP.. Nucleocytoplasmic transport: a role for nonspecific competition in karyopherin-nucleoporin interactions. Mol Cell Proteomics. 2012 May;11(5):31-46. doi: 10.1074/mcp.M111.013656. Epub 2012 Feb 22.

van der Waal MS, Hengeveld RC, van der Horst A, Lens SM.. Cell division control by the Chromosomal Passenger Complex. Exp Cell Res. 2012 Jul 15;318(12):1407-20. doi: 10.1016/j.yexcr.2012.03.015. Epub 2012 Mar 24. (REVIEW)

Atkinson CE, Mattheyses AL, Kampmann M, Simon SM.. Conserved spatial organization of FG domains in the nuclear pore complex. Biophys J. 2013 Jan 8;104(1):37-50. doi: 10.1016/j.bpj.2012.11.3823. Epub 2013 Jan 8.

Bui KH, von Appen A, DiGuilio AL, Ori A, Sparks L, Mackmull MT, Bock T, Hagen W, Andres-Pons A, Glavy JS, Beck M.. Integrated structural analysis of the human nuclear pore complex scaffold. Cell. 2013 Dec 5;155(6):1233-43. doi: 10.1016/j.cell.2013.10.055.

Cubenas-Potts C, Goeres JD, Matunis MJ.. SENP1 and SENP2 affect spatial and temporal control of sumoylation in mitosis. Mol Biol Cell. 2013 Nov;24(22):3483-95. doi: 10.1091/mbc.E13-05-0230. Epub 2013 Sep 18.

Cubenas-Potts C, Matunis MJ.. SUMO: a multifaceted modifier of chromatin structure and function. Dev Cell. 2013 Jan 14;24(1):1-12. doi: 10.1016/j.devcel.2012.11.020. (REVIEW)

Di Nunzio F.. New insights in the role of nucleoporins: a bridge leading to concerted steps from HIV-1 nuclear entry until integration. Virus Res. 2013 Dec 26;178(2):187-96. doi: 10.1016/j.virusres.2013.09.003. Epub 2013 Sep 16. (REVIEW)

Di Nunzio F, Fricke T, Miccio A, Valle-Casuso JC et al.. Nup153 and Nup98 bind the HIV-1 core and contribute to the early steps of HIV-1 replication. Virology. 2013 May 25;440(1):8-18. doi: 10.1016/j.virol.2013.02.008. Epub 2013 Mar 21.

Fitzgerald KD, Chase AJ, Cathcart AL, Tran GP, Semler BL.. Viral proteinase requirements for the nucleocytoplasmic relocalization of cellular splicing factor SRp20 during picornavirus infections. J Virol. 2013 Mar;87(5):2390-400. doi: 10.1128/JVI.02396-12. Epub 2012 Dec 19.

Gervais C, Dano L, Perrusson N, Helias C, Jeandidier E, Galoisy AC, Ittel A, Herbrecht R, Bilger K, Mauvieux L.. A translocation t(2;8)(q12;p11) fuses FGFR1 to a novel partner gene, RANBP2/NUP358, in a myeloproliferative/myelodysplastic neoplasm. Leukemia. 2013 Apr;27(5):1186-8. doi: 10.1038/leu.2012.286. Epub 2012 Oct 8.

Koh Y, Wu X, Ferris AL, Matreyek KA, Smith SJ, Lee K, KewalRamani VN, Hughes SH, Engelman A.. Differential effects of human immunodeficiency virus type 1 capsid and cellular factors nucleoporin 153 and LEDGF/p75 on the efficiency and specificity of viral DNA integration. J Virol. 2013 Jan;87(1):648-58. doi: 10.1128/JVI.01148-12. Epub 2012 Oct 24.

Matreyek KA, Yucel SS, Li X, Engelman A.. Nucleoporin NUP153 phenylalanine-glycine motifs engage a common

binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog. 2013;9(10):e1003693. doi: 10.1371/journal.ppat.1003693. Epub 2013 Oct 10.

Milles S, Huy Bui K, Koehler C, Eltsov M, Beck M, Lemke EA.. Facilitated aggregation of FG nucleoporins under molecular crowding conditions. EMBO Rep. 2013 Feb;14(2):178-83. doi: 10.1038/embor.2012.204. Epub 2012 Dec 14.

Ori A, Banterle N, Iskar M, Andres-Pons A et al.. Cell type-specific nuclear pores: a case in point for context-dependent stoichiometry of molecular machines. Mol Syst Biol. 2013;9:648. doi: 10.1038/msb.2013.4.

Shain AH, Salari K, Giacomini CP, Pollack JR.. Integrative genomic and functional profiling of the pancreatic cancer genome. BMC Genomics. 2013 Sep 16;14:624. doi: 10.1186/1471-2164-14-624.

Szymborska A, de Marco A, Daigle N, Cordes VC, Briggs JA, Ellenberg J.. Nuclear pore scaffold structure analyzed by super-resolution microscopy and particle averaging. Science. 2013 Aug 9;341(6146):655-8. doi: 10.1126/science.1240672. Epub 2013 Jul 11.

Tamura K, Hara-Nishimura I.. The molecular architecture of the plant nuclear pore complex. J Exp Bot. 2013 Feb;64(4):823-32. doi: 10.1093/jxb/ers258. Epub 2012 Sep 17. (REVIEW)

Umlauf D, Bonnet J, Waharte F, Fournier M, Stierle M, Fischer B, Brino L, Devys D, Tora L.. The human TREX-2 complex is stably associated with the nuclear pore basket. J Cell Sci. 2013 Jun 15;126(Pt 12):2656-67. doi: 10.1242/jcs.118000. Epub 2013 Apr 16.

Vognsen T, Moller IR, Kristensen O.. Crystal structures of the human G3BP1 NTF2-like domain visualize FxFG Nup repeat specificity. PLoS One. 2013 Dec 4;8(12):e80947. doi: 10.1371/journal.pone.0080947. eCollection 2013.

Wan G, Zhang X, Langley RR, Liu Y, Hu X, Han C et al.. DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM-AKT pathway. Cell Rep. 2013 Jun 27;3(6):2100-12. doi: 10.1016/j.celrep.2013.05.038. Epub 2013 Jun 20.

Xu S, Powers MA.. In vivo analysis of human nucleoporin repeat domain interactions. Mol Biol Cell. 2013 Apr;24(8):1222-31. doi: 10.1091/mbc.E12-08-0585. Epub 2013 Feb 20.

Yoshimura SH, Otsuka S, Kumeta M, Taga M, Takeyasu K.. Intermolecular disulfide bonds between nucleoporins regulate karyopherin-dependent nuclear transport. J Cell Sci. 2013 Jul 15;126(Pt 14):3141-50. doi: 10.1242/jcs.124172. Epub 2013 May 2.

Eisenhardt N, Redolfi J, Antonin W.. Interaction of Nup53 with Ndc1 and Nup155 is required for nuclear pore complex assembly. J Cell Sci. 2014 Feb 15;127(Pt 4):908-21. doi: 10.1242/jcs.141739. Epub 2013 Dec 20.

Fahrenkrog B.. Nucleoporin gene fusions and hematopoietic malignancies. New Journal of Science. 2014; 10: 1-18; doi 10.1038/leu.2008.80.

Vollmer B, Antonin W.. The diverse roles of the Nup93/Nic96 complex proteins - structural scaffolds of the nuclear pore complex with additional cellular functions. Biol Chem. 2014 May;395(5):515-28. doi: 10.1515/hsz-2013-0285. (REVIEW)


Duheron V, Fahrenkrog B. The nuclear pore complex: structure and function. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(5):355-375.



INIST-CNRS

OPEN ACCESS JOURNAL

Policies- Instructions to Authors

See http://documents.irevues.inist.fr/bitstream/handle/2042/48486/Instructions-to-authors.pdf

Manuscriptssubmitted to the Atlas must be submitted solely to the Atlas.

The Atlas publishes "cards", "deepinsights", "case reports", and "educationalitems".

Cards are structured review articles. Detailed instructionsfor these structured reviews can be found at:

http://AtlasGeneticsOncology.org/Forms/Gene_Form.html for reviews on genes,

http://AtlasGeneticsOncology.org/Forms/Leukaemia_Form.html for reviews on leukaemias,

http://AtlasGeneticsOncology.org/Forms/SolidTumour_Form.html for reviews on solid tumours,

http://AtlasGeneticsOncology.org/Forms/CancerProne_Form.html for reviews on cancer-prone diseases.

According to thelength of thepaper, cards are divided, into "reviews" (textsexceeding 2000 words), "mini reviews"

(between), and "short communications" (textsbelow 400 words).

Deep Insights are written as traditional papers, made of paragraphs with headings, at the author's convenience.

Case Reports in haematological malignancies are dedicated to recurrent –but rare- chromosomes abnormalities in

leukaemias/lymphomas; see http://atlasgeneticsoncology.org//BackpageAuthors.html#CASE_REPORTS .

It is mandatory to use the specific "Submissionformfor Case reports":

see http://AtlasGeneticsOncology.org/Reports/Case_Report_Submission.html.

Educationa lItems must be didactic, give full information and be accompanied with iconography.

Research articles The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.

Authorship All authors should qualify for authorship according to the ICMJE criteria.

Editorial Ethics see http://documents.irevues.inist.fr/bitstream/handle/2042/56068/Policies-editorial-ethics.pdf for: Peer Review Process /

Commissioned papers vs Unsolicited papers /Responsibility for the reviewers / Editorial responsibilities / Conflict of interest-

Competing interests / Privacy and Confidentiality - Iconography / Protection of Human Subjects and Animals in Research /

Duplicate Publication/ Plagiarism / Retracting a publication

SubscriptionThe Atlas isFREE!

Costs/Page Charge There is NO page charge.

PubMed Central Once the paper on line, authors are encouraged to send their manuscript to PubMed Central

http://www.ncbi.nlm.nih.gov/pmc/ with reference to the original paper in the Atlas in

http://documents.irevues.inist.fr/handle/2042/15655

Corporate patronage, sponsorship and advertising

Enquiries should be addressed to [email protected].

Rules, Copyright Notice and Disclaimer

http://documents.irevues.inist.fr/bitstream/handle/2042/48487/Copyright-sponsorship.pdf

Property As "cards" are to evolve with further improvements and updates from various contributors, the property of the

cards belongs to the editor, and modifications will be made without authorization from the previous contributor (who may,

nonetheless, be asked for refereeing); contributors are listed in an edit history manner. Authors keep the rights to use further

the content of their papers published in the Atlas, provided that the source is cited.

Copyright The information in the Atlas of Genetics and Cytogenetics in Oncology and Haematology is issued for general

distribution. All rights are reserved. The information presented is protected under international conventions and under

national laws on copyright and neighbouring rights. Commercial use is totally forbidden. Information extracted from the

Atlas may be reviewed, reproduced or translated for research or private study but not for sale or for use in conjunction with

commercial purposes. Any use of information from the Atlas should be accompanied by an acknowledgment of the Atlas as

the source, citing the uniform resource locator (URL) of the article and/or the article reference, according to the Vancouver

convention. Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or

otherwise, does not necessarily constitute or imply its endorsement, recommendation, or favouring. The views and opinions

of contributors and authors expressed herein do not necessarily state or reflect those of the Atlas editorial staff or of the web

site holder, and shall not be used for advertising or product endorsement purposes. The Atlas does not make any warranty,

express or implied, including the warranties of merchantability and fitness for a particular purpose, or assumes any legal

liability or responsibility for the accuracy, completeness, or usefulness of any information, and shall not be liable whatsoever

for any damages incurred as a result of its use. In particular, information presented in the Atlas is only for research purpose,

and shall not be used for diagnosis or treatment purposes. No responsibility is assumed for any injury and/or damage to

persons or property for any use or operation of any methods products, instructions or ideas contained in the material herein.

See also "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical

Publication - Updated October 2004": http://www.icmje.org.

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

http://atlasgeneticsoncology.org/Forms/Gene_Form.html

http://atlasgeneticsoncology.org/Forms/Leukemia_Form.html

http://atlasgeneticsoncology.org/Forms/SolidTumor_Form.html

http://atlasgeneticsoncology.org/Forms/CancerProne_Form.html%20for

http://atlasgeneticsoncology.org/BackpageAuthors.html#CASE_REPORTS

http://www.ncbi.nlm.nih.gov/pmc/

http://documents.irevues.inist.fr/handle/2042/15655


http://documents.irevues.inist.fr/bitstream/handle/2042/48487/Copyright-sponsorship.pdf

http://www.icmje.org/

http://www.atlasgeneticsoncology.org/



INIST-CNRS

OPEN ACCESS JOURNAL

documents.irevues.inist.frdocuments.irevues.inist.fr/bitstream/handle/2042/... · in Oncology and Haematology The PDF version of the Atlas of Genetics and Cytogenetics in Oncology

Documents