cell adhesion
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Cell AdhesionCell Adhesion
黃敏銓黃敏銓mchuang@ntu.edu.tw
G d t I tit t f A t d C ll Bi l1
Graduate Institute of Anatomy and Cell Biology
CellCell--Cell Adhesion and CellCell Adhesion and Cell--Matrix AdhesionMatrix Adhesion
actinfilaments
cadherinadhesion belt(cadherins)
filaments
Ig CAMs
integrinl tiselectin
focal contactintegrin
focal contact(integrins)
2
Functions of Cell Adhesioncell cycle
proliferation migration
differentiation survival
Cell Adhesion
inflammation cell shape
angiogenesis polarity
3apoptosis
CELL-CELL ADHESIONCadherins E, N, P Ca2+- or Mg2+
-dependencehomophilic actin filaments (via adhesion belts
cadherins -dependence catenins)
desmosomal cadherins
yes homophilic intermediate filaments (via desmoplakins,
desmosomes
desmoplakins, plakoglobin and other proteins)
Ig family members N-CAM, L1 no homophilic or h t hili
unknown noheterophilic
Selectins (blood cells + endothelial cells)
P-selectin yes heterophilic unknown no
Integrins (on blood cells) LFA 1 (a b ) yes heterophilic actin filaments noIntegrins (on blood cells) LFA-1 (aLb2), Mac-1 (aMb2)
yes heterophilic actin filaments no
CELL-MATRIX ADHESIONIntegrins many types yes heterophilic actin filaments
(via talin, vinculin, and other proteins)
focal contacts
proteins)
a6b4 yes heterophilic intermediate filaments
hemidesmosomes
Transmembrane syndecans no heterophilic actin filaments no
4
Transmembrane Proteoglycans
syndecans no heterophilic actin filaments no
Major families of cell-adhesion molecules
5
6
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
7
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
Significance of cytoskeletons in cell adhesion
ith tadhesion molecule
Plasma membrane
No effect on cellwithout
cytoskeletalattachment
PULL
cytoskeleton
withcytoskeletal
Cell adhesiony
attachment
8PULL
Cell-Cell adhesionCell Cell adhesion
9
Ig CAMs
endothelium
109
SelectinP-selectin
EGF-like domain
Lectin domain
E-selectinse ec
Short consensus repeatL-selectin
Short consensus repeat
11
LEUKOCYTE
P Selectin
L-Selectin
P-Selectin E-Selectin
ENDOTHELIAL CELLS
ThrombinHistamineTNF- LPS
TNF- IL-1 IFN-
12
LPS LPS
L-Selectin ESL-1 PSGL-1
LEUKOCYTE
L-Selectin ESL 1 PSGL 1
h
ENDOTHELIAL CELL
E-SelectinGlyCAM-1 MAdCAM-1CD34 P-Selectin
13
INTERACTIONINTERACTION
Selectin Selectin Ligandlipids
Protein Carbohydrate on lipids
proteinsp
14
Leukocyte Adhesion Deficiency II (LAD II)
I t t i th t d tiIntrauterine growth retardation
Recurrent infection
Mental retardation
Short statureNat Genet. 2001. 28:69-72
Mutation in GDP-fucose transporterAutistic features
Convulsions
Mutation in GDP fucose transportercauses no fucose at the cell surface.
Cerebral atrophy
Microcephaly
a 20-year-old manwith LAD II
Coarse face
J Clin Immunol. 2010 Mar;30(2):308-13.15
Leukocyte Adhesion Deficiency IIIy y
16
Nature Medicine 15, 249 - 250 (2009)
Cell-ECM adhesionCell-ECM adhesion
17
IntegrinIntegrin
18Cell, Vol. 110, 673–687, September 20, 2002
Signaling transduction pathways emanating from Integrinsfrom Integrins
1931 MAY 2002 VOL 296 p.1652-1653 SCIENCE
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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 2 | NOVEMBER 2001 | 795
Common integrins and ECM ligands bound
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Journal of Cell Science 115, 3729-3738 © 2002
Integrin binding proteins
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Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
Integrin binding proteinsIntegrin binding proteins
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Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
Integrin Signaling Pathway
Integrins
24
http://stke.sciencemag.org May 31, 2002. J. Thomas Parsons
FAKFAKFocal Adhesion Kinase
25
26
Oncogene (2004) 23, 7928–7946.
Focal Adhesion Kinase (FAK)t t i kinonreceptor tyrosine kinase
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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 6 | JANUARY 2005 | 59
Example of FAK function
caveolin
Focal Adhesion Kinase ShcP P
CrkII
C3GRas
Ras
Rap-1 Raf
survival
ERK
B-Raf
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Modified from Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
ERKERK
contractibility
Multiple signaling proteins dock at Tyrosine 397 of FAKTyrosine 397 of FAK
pY397p
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Biochimica et Biophysica Acta 1540 (2001) 1-21
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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 6 | JANUARY 2005 | 58
Mock IB:β4GalNAc T3A B
Mock
4G10
IB:β4GalNAc-T3
pY397
IB:Mock β4GalNAc-T3
1.0 2.5
β4GalNAc-T3
1.0 2.54G10(anti-pY)
1.0 2.7
FAK
pY576
1.0 1.7PY20(anti pY)
FAKIP: FAK (C20)
FAK(anti-pY)1.0 3.5
DIP: FAK (C20)
IB:Mock β4GalNAc-T3C
D
pERK1/2
Mock β4GalNAc-T3
pY118-paxillin
pY31-paxillin
1.0 1.8 ERK1/2
1.0 1.8
paxillin
pY31 paxillin
1.0 0.5
WCL
β-actin
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ILKILKIntegrin-Linked Kinase
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Integrin Linked Kinase binding proteinsIntegrin-Linked Kinase binding proteins
33
The Journal of Cell Biology, Volume 155, Number 4, November 12, 2001 505-510
ILK-PINCH-parvin (IPP) complex
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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 7 | JANUARY 2006 | 22
Signaling through IPP complex
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NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 7 | JANUARY 2006 | 24
36NATURE REVIEWS | CANCER VOLUME 5 | JANUARY 2005 | 60
Activation of MAP kinaseActivation of MAP kinase cascades by integrinscascades by integrins
37
Activation of MAP kinase cascades by integrins
caveolin
Focal Adhesion Kinase ShcP P
CrkII
C3GRas
Ras C3G
Rap-1 Raf
survival
Ras
ERK
B-Raf
survival
38
Modified from Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
ERKERK
contractibility
Integrin regulates actin filamentsIntegrin regulates actin filamentsformation via Rho GTPases
(Rh R CDC42)(Rho, Rac, CDC42)
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Integrin signaling to the cytoskeleton via Rho GTPases
Rho Rac CDC42
Pcofilin
STRESS FIBERS
40
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
Mechanism of activation of N-WASP
P Active N-WASP
41Adapted from Journal of Cell Science 114, 1801-1809, 2001
Mechanism of activation of WAVE2
42Journal of Cell Science 114, 1801-1809, 2001
Cooperativity between growth-factor receptors and integrins
growth factor receptorintegrin
43
NATURE CELL BIOLOGY VOL 2 DECEMBER 2000 E225-229
Integrin regulates signaling in RTK/Ras/MAPK pathway
integrin Receptor Tyrosine Kinase
1
2
cytoplasm1 cytoplasm
33
nucleus
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Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
1. Activation of receptor tyrosine kinase (RTK)
I t i ti d li d bi di• Integrin aggregation and ligand binding
– EGFR, PDGF-R, FGFR phosphorylation
• Integrin aggregation alone
– PDGF-R, EGFR
• Direct integrin-RTK interaction
– v3 and PDGF-R, insulin receptor,
VEGF-R2
• Via integrin-associated cytoskeletal
components
– Integrin-actin-Neu RTK, integrin-FAK-
45EGFR or PDGFR
Integrin regulation of growth factor receptors
46
NATURE CELL BIOLOGY VOL4 APRIL 2002 E75-76
FAK integrates growth-factor and integrin signals to promote cell migrationg p g
47Current Opinion in Genetics & Development 2004, 14:92–101
2. Coupling between upstream and downstream molecules
Between Ras-Raf
– EGFR, PDGF-R in
anchorage-dependent
cell growthcell growth
48
3. Transmission of the signal from cytoplasm to nucleus
J Cell Biol 2001 Apr 16;153(2):273-82
• Integrin mediated adhesion• Integrin-mediated adhesion Regulates ERK Nuclear Translocation andTranslocation and Phosphorylation of Elk-1– Actin cytoskeleton-
dependent (NIH 3T3 cells)
– G1 phase progression
49
Examples of synergisms between integrins and RTK i liRTK signaling
50
Annu. Rev. Pharmacol. Toxicol. 2002. 42:283–323
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