Function of NF2/Merlin in regulation of the Hippo/Salvador/Warts growth control pathway

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Project Summary/Abstract Neurofibromatosis type 2 (NF2), a human 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. Studies using the fruit fly Drosophila and subsequently confirmed in mammalian systems indicate that Merlin is an upstream component of the Hippo pathway, a conserved signal transduction pathway that regulates tissue growth. Mutations in Merlin and other Hippo 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 and how the activity of this complex is controlled. We have shown that Merlin and its binding partner 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 have shown that as these proteins assemble a signaling complex, they recruit an E3-ligase complex that degrades Kibra and represses signaling in a negative feedback loop. In the next funding period, we propose that Kibra degradation is promoted by mechanical tension and that this is one mechanism by which tension controls tissue growth. We also plan to test a model we propose in which Kibra and Merlin are recruited to the junctional cortex in an inactive state by the apical polarity protein aPKC in opposition to medial actomyosin networks which facilitate medial accumulation and activation of these proteins. To explore these novel hypotheses, we have developed tools and techniques that allow us to examine the localization and dynamics of Hippo 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 Hippo pathway. These experiments are expected to provide insights into NF2, tumor suppression in general, and the role of actomyosin dynamics in regulating signaling processes. 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.