The NF2 Tumor Suppressor Merlin and the ERM Proteins Interact with N-WASP and Regulate Its Actin Polymerization Function

Abstract

The function of the NF2 tumor suppressor merlin has remained elusive despite increasing evidence for its role in actin cytoskeleton reorganization. The closely related ERM proteins (ezrin, radixin, and moesin) act as linkers between the cell membrane and cytoskeleton, and have also been implicated as active actin reorganizers. We report here that merlin and the ERMs can interact with and regulate N-WASP, a critical regulator of actin dynamics. 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 the 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.

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

“…Ezrin, another member of the ERM family, is reported to participate in Src signaling and to induce FAK activation (Poullet et al, 2001;Srivastava et al, 2005) Although ezrin and merlin have similarities in structure and common interacting partners, such as CD44, NHERF and N-WASP (Bretscher et al, 2000;Morrison et al, 2001;Martin et al, 2003;Manchanda et al, 2005), they possess opposite functions in cell growth and proliferation. As we observed an inhibitory effect of merlin on cell migration and invasion, we sought to determine if merlin could downregulate FAK.…”

Tumor-suppression functions of merlin are independent of its role as an organizer of the actin cytoskeleton in Schwann cells

“…Indeed, its binding partners include those that regulate transport (Murthy et al, 1998;Scoles et al, 2006;Shenolikar and Weinman, 2001), translation (Scoles et al, 2006), cell-cycle transit (Gronholm et al, 2006), cell-cell adhesion (Gutmann et al, 1999;Lallemand et al, 2003;Morrison et al, 2001;Obremski et al, 1998), cytoskeletal organization (Bashour et al, 2002;Manchanda et al, 2005), and signaling (Kissil et al, 2003;Okada et al, 2005;Rong et al, 2004b). However, at this juncture it is unclear which of these interactions are essential for merlinmediated inhibition of cell proliferation and tumor growth.…”

Nf2/Merlin: a coordinator of receptor signalling and intercellular contact

“…The disorganised actin cytoskeleton observed in some Nf2 À/À cells could reflect the ability of Merlin to anchor actin to the membrane, to inhibit signals that maintain a highly dynamic actin cytoskeleton, or both. For example, Merlin can inhibit both Arp2/3- (Manchanda et al, 2005) and Rac-induced actin assembly (Pelton et al, 1998).…”