The role of the Neurofibromatosis 2 tumor suppressor merlin and the related ERM proteins in signaling to the actin cytoskeleton

The Neurofibromatosis 2 tumor suppressor merlin and the related ERM proteins (ezrin, radixin and moesin) and have been well characterized as linkers between the cell membrane and cytoskeleton. Increasing evidence, however, implicates these proteins as active actin reorganizers. This dissertation reports that merlin and ERMs can interact with and regulate N-WASP, a critical regulator of actin dynamics. This interaction occurs in vitro and in vivo through the FERM domain of merlin/ERMs and the WH1 (WASP Homology 1)/EVH1 (Ena/Vasp Homology 1) domain of N-WASP. Merlin and moesin were found to inhibit N-WASP-mediated actin assembly in vitro, a function that appears independent of their ability to bind actin. Furthermore, exogenous expression of a constitutively active ERM inhibits N-WASP dependent Shigella tail formation, suggesting that ERMs may function as inhibitors of N-WASP function in vivo. This novel function of merlin and the ERMs illustrates a mechanism by which these proteins directly exert their effects on actin reorganization and also provides new insight into N-WASP regulation. These findings are relevant for the cytoskeletal abnormalities observed in cells derived from NF2 patients and might explain some of the tumor suppressor function of merlin.