Project Summary/Abstract Neurofibromatosis type 2 (NF2), a dominantly inherited disease characterized by the formation of bilateral vestibular Schwannomas (resulting in deafness) and other tumors, is caused by loss of the tumor suppressor protein Merlin, a member of the FERM domain superfamily. Studies using the fruit fly Drosophila and subsequently confirmed in mammalian systems indicate that Merlin is an upstream component of the Hippo/Salvador/Warts (HSW) pathway, a conserved signal transduction pathway that regulates tissue growth. Mutations in Merlin and other HSW pathway components are believed to cause tumors because they cause activation of an oncogenic protein Yorkie/YAP and increased expression of growth promoting genes. Identifying specific proteins and signal transduction pathways with which Merlin interacts is especially important because these partners may act as genetic modifiers of NF2 disease phenotypes and provide potential targets for therapeutic agents. We seek to understand how Merlin and the other HSW components are organized into a signaling complex at the cell cortex, what controls the activity of this complex, and how feedback regulation operates within the pathway. We propose that Merlin and Kibra nucleate formation of a signaling complex at a site separate from intercellular junctions, and thus that these proteins can function in parallel to another upstream regulator, Expanded. We also plan to study how cortical tension regulates pathway activity, and in turn how pathway activity might control cortical tension. To address these questions, we have developed tools and techniques that allow us to examine the localization and dynamics of HSW pathway proteins expressed at endogenous levels in living tissues. Using with the exquisite genetic tools available in Drosophila, we can now elucidate the role of each pathway component in assembling and activating the HSW pathway. These experiments are expected to provide insights into NF2, tumor suppression in general, and the normal cellular processes that establish specialized membrane domains in epithelial cells and neurons. Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control tissue growth and determine cell fate during development and regeneration.

R56NS034783

1996-01-01

2017-07-31