NF2: A Tumor Suppressor NF2 encodes Merlin/Schwannomin, a protein that regulates cell growth and proliferation.
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NF2: A Tumor Suppressor
NF2 encodes Merlin/Schwannomin, a protein that regulates cell growth and
proliferation
NF2: A Tumor Suppressor
Mutations in NF2 can cause Neurofibromatosis Type II, a cancer
affecting the auditory nerve and other central nervous system tissues.
NF2 is located on chromosome 22
www.genome.ou.edu
bioweb.wku.edu
NF2’s protein product, merlin, serves to limit cell proliferation in
several ways:
1. It regulates cytoskeletal anchorage to neighboring cells and the cell matrix.
NF2’s protein product, merlin, serves to limit cell proliferation in
several ways:
1. It regulates cytoskeletal anchorage to neighboring cells and the cell matrix.
2. It blocks the ras pathway.
NF2’s protein product, merlin, serves to limit cell proliferation in
several ways:
1. It regulates cytoskeletal anchorage to neighboring cells and the cell matrix.
2. It blocks the ras pathway.
3. It inhibits cyclin D and progression of the cell cycle.
How does merlin interact with the cytoskeleton?
To answer that, we need to meet a few of its relatives…
Merlin is related to the ERM proteins• The ERM (Ezrin, Radixin, Moesin) family is a group of
membrane and cytoskeleton associated proteins.
McClatchey, A.I., et.al.
Merlin and the ERMs are fairly similar in sequence. They share a FERM domain that allows them to
localize to the plasma membrane.
Gutmann and Giovannini
Merlin is related to the ERM proteins• RHOA belongs to a family of GTPases whose activation
induces phosphorylation/activation of the ERM proteins
McClatchey et.al.
•RAC1 is another member of the RHO-GTPase family, but its activation leads to the
phosphorylation/inactivation of merlin.
McClatchey, A.I.
OnOff
Merlin is related to the ERM proteins
Mutant NF2 allows cell over-proliferation and possibly cell motility by de-polarizing cells and releasing cell-cell and cell-matrix junctions
McClatchey, A.I.
Loss of Merlin
Normal function of ERM Proteins
Remember that Adherens junctions glue cells together and also connect their actin cytoskeletons.
Plasma membrane
Intracellular
Extracellular
DE-cadherin
Armadillo-catenin
F-actinIntracellular
Plasma membrane
Merlin
Plasma membrane
Intracellular
Extracellular
DE-cadherin
Armadillo-catenin
F-actinIntracellular
Plasma membrane
In addition to regulating actin polymerization, merlin and other proteins stabilize adherens junctions.
Merlin
Cells that are mutant in both copies of NF2 do not form functional cell-cell or cell-matrix
junctions…
Lallemand, D., et.al.
Bright green is ß-catenin
Neurofibromatosis Type II
• The gene NF2 gets its name from the type of cancer it causes: Neurofibromatosis Type II
Neurofibromatosis Type II
• The penetrance of NF2 is over 95%
Zucman-Rossi, J., et.al.R. Weinberg, Cancer Biology
DNA screens can identify patients who have no symptoms
NF2 mutations in tumor cells are usually deletions; the mutant gene will be smaller than wild type.
Warren, C., et.al.www.stanford.edu
Vestibular Schwannomas (Acoustic Neuromas) are
unequivocal indicators of NF2
www.nfinc.org
These tumors often lead to deafness.
Works Cited:McClatchey, A.I., et.al. “The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation”. Genes and Development. 10. (1997): 1253-65.
Gutmann, D.H., and Giovannini, M. “Mouse Models of Neurofibromatosis 1 and 2”. Neoplasia. 4(2002): 279-90.
Zucman-Rossi, J., et.al. “Exhaustive characterization of the NF2 gene in neurofibromatosis type 2 patients”. Human Molecular Genetics. 7 (1998): 2095-2101.
Baser, M.E., et.al. “Predictors of the Risk of Mortality in Neurofibromatosis Type II”. American Journal of Human Genetics. 71 (2002): 715-723
McClatchey, A.I., “Merlin and ERM Proteins: Unappreciated Roles in Cancer Development?”. Nature Reviews, Cancer. 3 (2003): 877-84.
Lallemand, D., et.al., “NF2 Deficiency Promotes Tumorigenesis and Metastasis by Destabilizing Adherens Junctions”. Genes and Development. 17 (2003): 1090-1100.
Warren, C., et.al., “Identification of Recurrent Regions of Chromosome Loss and Gain in Vestibular Schwannomas Using Comparative Genomic Hybridization”. Journal of Medical Genetics. 40 (2003): 802-6.
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