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Adam David Gracz

NF2/Merlin Normal Functions and implications in cancer biology. Adam David Gracz. Normal Function. Tumor Suppressor. NF2 = gene Merlin = protein…a.k.a. schwannomin. Tumor suppressive ability comes from partial inhibition of Ras/Rac signaling (phosphorylates in the presence of Ras/Rac).

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Adam David Gracz

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  1. NF2/Merlin Normal Functions and implications in cancer biology Adam David Gracz

  2. Normal Function Tumor Suppressor • NF2 = gene • Merlin = protein…a.k.a. schwannomin • Tumor suppressive ability comes from partial inhibition of Ras/Rac signaling (phosphorylates in the presence of Ras/Rac).

  3. Normal Function • Similar to ERM family of proteins : membrane-cytoskeleton linking proteins • Strong evidence of a role in cell motility and proliferation Sun, et. al. Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation. Journal of Cell Science 2002: 115, 3991-4000

  4. Normal Function Sun, et. al. Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation. Journal of Cell Science 2002: 115, 3991-4000 • Is considered functionally active in “closed” state – N- (FERM domain) and • COOH-terminals self-associate. • Serine phosphorylation at COOH-terminus prevents self-association, Merlin • is in “open state” and therefore functionally inactive.

  5. Normal Function • Helps regulate signaling in RhoGTPases (Rho, Rac, and Cdc42). These factors • control cell motility and matrix adhesions. Sun, et. al. Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation. Journal of Cell Science 2002: 115, 3991-4000

  6. What goes wrong • Neurofibromatosis type II is autosomal dominant • Follows Knudson’s “two-hit” hypothesis: • One allelic mutation from parent • One somatic allelic mutation

  7. What goes wrong • Loss of function also observed in sporadic tumors (i.e. non-neurofibromatosis type II patients). • Proposed model of tumor suppressive function involves phosphorylation • of Merlin by kinase cascade initiated through Rho/Rac

  8. What goes wrong Sun, et. al. Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation. Journal of Cell Science 2002: 115, 3991-4000

  9. What goes wrong Increased cell growth/survival/motility! Sun, et. al. Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation. Journal of Cell Science 2002: 115, 3991-4000

  10. Finding NFR2 • Mouse models that are doubly deficient of NF2 (genotype NF2-/-) exhibit lethality in the embryonic stage (days 6.5-7: high specificity). Wild-type Homozygous mutant McClatchey, et al. The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation. Genes & Dev. 1997 11: 1253-1265

  11. Finding NFR2 • Mouse models with one mutated allele of NF2 (genotype NF2+/-) exhibit extensive, multi-systemic tumors with a high rate of metastasis.

  12. Finding NFR2 • Tissue deficient of Merlin loses ability to form cadherin mediated • cell-cell junctions. McClatchey, Merlin and ERM proteins: unappreciated roles in cancer development? Nature Reviews Cancer Nov. 2003 877-883 • Cells expressing aberrant Ras exhibit contact inhibition. This • property can be “rescued” by the addition of wild-type Merlin.

  13. Clinical Presentations Classic manifestation = MISME: Multiple Inherited Schwannomas, Meningiomas, Ependymomas Bilateral Vestibular Schwannoma (Acoustic neuroma) Xiao, et. al. Chinese Medical Journal, 2007, Vol. 120 No. 16 : 1456-1459 Meningioma Tuburculum Sella Meningioma: http://www.cornellneurosurgery.org/endoscopicskullbase/Meningiomas.htm

  14. Clinical Presentations Spinal ependymoma – intradural-extramedullary Mesothelioma Ependymoma of the Lumbar Spine: http://www.columbiaspine.org/patients/disease/spinal_tumors.html History: Cough: http://www.radiology.vlahos.org/45391/47473.html

  15. Therapies and Outlook • Observation if tumors diagnosed early • Cochlear implants to compensate for hearing loss (vestibular schwannomas) • Surgical resection or decompression • Stereotactic radiosurgery

  16. Therapies and Outlook • Clinical trial for vatalanib in progress at Northwestern University: -patient must be an adult -works as a protein tyrosine kinase inhibitor targeting tumor angiogenesis – nonspecific to NF2/Merlin • Precise pathway and interaction with other signaling cascades remains unclear.

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