Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by development of Schwann cell tumors of the eighth cranial nerve. The NF2 gene encodes a protein named merlin, which is highly related to the ERM proteins (moesin, ezrin and radixin). Merlin is phosphorylated by Paks, which bind to activated (GTP-bound) Rac/Cdc42 and function as their direct effectors. Recent data implicate that merlin negatively regulates Rac/cdc42 signaling by directly interacting with and inhibiting Paks. The proposed project is geared towards establishing whether the Pak-inhibitory function of merlin is also merlin's tumor suppressive function. Furthermore, cellular and animal models will be employed to test whether inhibiting Pak function can reverse the transformed and cancer phenotypes that arise from NF2 deficiency. Finally, experiments will be carried out to identify additional mechanisms that may contribute to NF2 tumor suppressor function. Taken together, these studies will lead to a better understanding of merlin's tumor suppressive function. The validation of Paks as potential targets for inhibition, stemming from these studies, will point directly at approaches for the development of therapeutics towards the treatment of neurofibromatosis type 2. ? ? ? ?
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