How Wasp Regulates Actin Polymerization

Protrusion of lamellipodia and filopodia from the cell surface requires that actin polymerize locally. Actin polymerization is initiated by numerous agonists, including growth factors, chemoattractants, extracellular matrix, and phagocytic particles. The signaling pathways from the corresponding receptors converge on Rho family GTPases, especially Rac and Cdc42, which induce actin polymerization through a family of proteins called WASP (WiskottAldrich Syndrome protein) 1 (Higgs and Pollard 1999). In mammals, the family includes WASP (specific to hematopoietic cells), N-WASP (neural WASP, which is actually ubiquitous), and at least four forms of WAVE (WASP verprolin homologous protein). The conserved COOH terminus of these proteins stimulates the Arp2/3 complex to nucleate actin filaments, which then elongate at their free barbed ends (Machesky et al., 1999). Two papers in this issue (Higgs and Pollard, 2000: Rohatgi et al., 2000) advance our knowledge of how WASP proteins regulate actin. First, although it was previously known that recombinant N-WASP can be stimulated by Cdc42 to activate nucleation, recombinant WASP, however, is constitutively active and thus is not regulated by a Rho-GTPase (Yarar et al., 1999). Now Higgs and Pollard (2000) have isolated native WASP from thymus and shown that it is indeed inactive until stimulated. Second, the known binding of N-WASP’s COOH terminus by its NH 2 terminus has now been shown to inhibit the ability of the COOH terminus to activate actin nucleation; this illuminates the molecular basis of this regulation (Higgs and Pollard, 2000; Rohatgi et al., 2000). Knowing that WASP stimulates actin polymerization, a key question is: what regulates WASPs? Recent results suggest that WASPs, like many proteins, are self-regulating, i.e., they contain both effector and regulatory domains (Fig. 1). The effector is the COOH-terminal VCA (verprolin homology, cofilin homology, acidic) domain, which is sufficient to activate nucleation (Machesky et al., 1999). A likely regulator is the NH 2 terminus GTPase binding domain (GBD; Miki et al., 1998). The NH 2 terminus also binds PIP 2 and WASP interacting protein (WIP; Miki et al., 1996; Ramesh et al., 1997). Between the GBD and VCA lies a proline-rich domain (PRD) that binds profilin as well as several proteins containing src homology 3 (SH3) domains (Brunnell et al., 1996; Finan et al., 1996). Any of these factors binding to a WASP might enhance or inhibit its activity.