Neurofibromatosis type 2 (NF2), a dominantly inherited disease, has been shown to be caused by mutations in Merlin (Schwannomin), a member of the protein 4.1 superfamily. Symptoms of NF2, which usually appear by early adult life, are caused by the formation of bilateral vestibular Schwannomas and other benign tumors. The cellular functions of Merlin and its role in tumor suppression are still largely unknown. Identifying specific proteins and signal transduction pathways with Merlin interacts is especially important because these partners may act as genetic modifiers of NF2 disease phenotypes and provide potential targets for therapeutic agents. The common fruit fly, Drosophila, has proven to be a useful model system for identifying genetic modifiers of gene function. The overall goal of this proposal is therefore to examine the cellular functions of Merlin and Drosophila, identify the proteins with which it interacts, and examine the relationship between Merlin and the closely related Ezrin/Radixin/Moesin proteins. In the next funding period, we plan to continue our studies of Merlin function in developing organisms in individual cells. Specifically, the proposed experiments will: 1) Examine the mechanisms by which Merlin function is regulate using a combination of in vitro mutagenesis and cellular nad biochemical analysis of protein function. 2) Identify second site modifiers of Merlin function by screening for mutations that enhance or suppress the phenotypes of dominant-negative Merlin transgenes. 3) Elucidate the functions of ERM proteins and their functional relationship with Merlin by isolating and characterizing mutations in the Drosophila Moesin gene. These experiments are expected to provide insights into the functions of Merlin and the ERM proteins. Thus they will contribute to our understanding of human NF2, tumor suppression in general, and carcinogenesis. In addition, the proposed experiments should lead to a better understanding of cellular processes that occur in the apical junctional domain. Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control cell growth and determine cell fate during development.
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