Integration with WASPs

Abstract

Many signaling pathways control cell shape, and these pathways ultimately do so, at least in part, by regulating polymerization of actin. Members of the WASP (Wiskott-Aldrich syndrome protein) family appear to integrate such signals and are thus subject to a complex array of regulatory mechanisms. Activation of WASP through the Rho family GTPase Cdc42 and interaction with phosphatidylinositol 4,5-bisphosphate (PIP 2 ) stimulate the Arp2/3 complex, which in turn promotes nucleation of actin filaments. Papers by Higgs and Pollard and Rohatgi et al . characterizing native WASP from bovine thymus and in vitro-translated N-WASP (where N refers to neuronal, even though this family member is widely expressed) and the Commentary by Zigmond provide new details of this multifaceted regulation. The NH 2 -terminus of WASP appears to interact with the COOH-terminus and block binding to Arp2/3. Activation by Cdc42 and PIP 2 reduces the autoinhibitory binding and exposes the Arp2/3 binding region. Rohatgi et al . use a mutant N-WASP insensitive to PIP 2 but sensitive to Cdc42 to show that the critical function of PIP 2 may actually be to activate Cdc42. Higgs and Pollard provide evidence that clustering of PIP 2 and Cdc42 on a membrane surface is important for efficient activation. Still more is to come, as investigators factor in the association of WASP proteins with receptors, viral proteins, other cytoskeletal proteins (profilin), and so on. Higgs, H.N., and Pollard, T.D. (2000) Activation by Cdc42 and PIP 2 of Wiscott-Aldrich Syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex. J. Cell Biol. 150 : 1311-1320. [Abstract] [Full Text] Rohatgi, R., Ho, H.-y.H., and Kirschner, M.W. (2000) Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4,5-biphosphate. J. Cell Biol. 150 : 1299-1309. [Abstract] [Full Text] Zigmond, S.H. (2000) How WASP regulates actin polymerization. J. Cell Biol. 150 : F117-F119. [Full Text]