• 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, 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.

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

• 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

• 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, 3991-4000

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

• Mouse models that are doubly deficient of NF2 (genotype NF2-/-) exhibit lethality in the embryonic stage (days 6.5-7: high specificity).

Wild-type Homozygousmutant

McClatchey, et al. The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation. Genes & Dev. 1997 11: 1253-1265

• 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. 2003 877-883

Bilateral Vestibular Schwannoma(Acoustic neuroma)

Xiao, et. al. Chinese Medical Journal, 2007, Vol. 120 No. 16 : 1456-1459

Classic manifestation = MISME: Multiple Inherited Schwannomas, Meningiomas, Ependymomas

Meningioma

Tuburculum Sella Meningioma: http://www.cornellneurosurgery.org/endoscopicskullbase/Meningiomas.htm

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

• 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.