Little is known about the molecular pathogenesis of nervous system tumors such as meningiomas and schwannomas. Individuals affected with neurofibromatosis 2 (NF2) develop these tumors at increased frequency. In addition, mutations and loss of NF2 gene expression are associated with the development of sporadic schwannomas and meningiomas, suggesting that the NF2 gene product, merlin is a critical growth regulator for Schwann cells and meningeal cells. The NF2 tumor suppressor gene bears sequence similarity to Protein4.1 proteins that link the actin cytoskeleton to cell surface glycoproteins. Previous work from out laboratory has demonstrated that merlin regulates cell motility and proliferation as well as cell spreading. In this application we propose to test the hypothesis that merlin integrates several different several cellular processes important for tumor formation and progression reflected by its ability to regulate cell spreading (tumor initiation), cell proliferation (tumor growth) and cell motility (tumor spread). The experiments proposed in this application are aimed at determining how the merlin tumor suppressor functions as a negative growth regulator by defining merlin functional domains, critical merlin protein interactions and relevant intracellular signaling pathways. Our ability to design rational therapies for schwannomas and meningiomas is dependent on an improved understanding of the mechanisms by which loss of merlin expression and function promotes tumor formation.
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