Molecular Function of the Nf2 Tumor Suppressor, Merlin

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DESCRIPTION (provided by applicant): Mutations in the NF2 tumor suppressor gene underlie Neurofibromatosis type 2 (NF2), a familial cancer syndrome featuring the development of central nervous system tumors. The NF2-encoded protein, Merlin, is closely related to the ERM (Ezrin, Radixin and Moesin) proteins, which are thought to facilitate the assembly of membrane:actin cytoskeleton complexes. However, the mechanism whereby Merlin controls cell proliferation is not known. To create an animal model for Nf2-associated tumorigenesis and develop tools for defining the molecular function of Merlin, we generated an Nf2-mutant strain of mice and found that Nf2 mutation predisposes mice to a variety of highly metastatic cancers. This is surprising given the limited spectrum of benign tumors in human NF2 patients and suggests that Nf2 inactivation may play an unrecognized role in cancer development and progression. Our broad objective is to use Nf2-mutant mice and cells to delineate the function of Merlin and its family members in cancer development and progression. We have recently found that a signature of Nf2-deficiency across several types of primary cells is loss of contact-dependent inhibition of proliferation and lack of normal cadherin-mediated cell:cell communication. We discovered that Merlin localizes to cadherin-containing adherens junctions (AJs) in wild-type cells and is required for the establishment of the final actin cytoskeleton associated AJ structure. We also found that silencing of the epidermal growth factor receptor (EGFR) at high cell density, which is known to be mediated by AJ establishment, is defective in the absence of Merlin. The goals of this proposal are to determine whether control of AJ establishment and EGFR silencing is the cellular mechanism whereby Merlin acts as a tumor and metastasis suppressor and to delineate the mechanism of Merlin function in AJ establishment. The results of this study will yield important insight into the mechanism of Merlin function as a tumor suppressor and identify novel targets for therapeutic intervention of NF2.