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

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

5. 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. Neurofibromatosis type II is autosomal dominant Follows Knudson’s “two-hit” hypothesis: – One allelic mutation from parent – One somatic allelic mutation

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

9. 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. Mouse models that are doubly deficient of NF2 (genotype NF2-/-) exhibit lethality in the embryonic stage (days 6.5-7: high specificity). Wild-typeHomozygous 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. Mouse models with one mutated allele of NF2 (genotype NF2+/-) exhibit extensive, multi-systemic tumors with a high rate of metastasis.

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

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

14. 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. Observation if tumors diagnosed early Cochlear implants to compensate for hearing loss (vestibular schwannomas) Surgical resection or decompression Stereotactic radiosurgery

16. 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.