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).

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,

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,

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,

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

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

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

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,

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 :

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

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

Bilateral Vestibular Schwannoma (Acoustic neuroma) Xiao, et. al. Chinese Medical Journal, 2007, Vol. 120 No. 16 : Chinese Medical Journal, 2007, Vol. 120 No. 16 Classic manifestation = MISME: Multiple Inherited Schwannomas, Meningiomas, Ependymomas Meningioma Tuburculum Sella Meningioma:

Spinal ependymoma – intradural-extramedullary Mesothelioma Ependymoma of the Lumbar Spine: History: Cough:

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

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.