Signaling to Actin Dynamics

Address correspondence to Laura Machesky, Department of Biochemistry, University of Birmingham, Birmingham B15 2TT, UK. Tel: 44-121414-2504. Fax: 44-121-414-3982. E-mail: [email protected] or [email protected] T HE actin cytoskeleton of a eukaryotic cell is central to locomotion, phagocytosis, contractility, shape changes, cytokinesis and maintenance of polarity. The mechanisms through which actin coordinates these different activities have been fascinating for many years, but the pace of discovery has recently been especially rapid. This review will concentrate on how cells control actin polymerization to produce the force for motility and shape changes. It is becoming clear that the Arp2/3 1 complex, a complex of seven proteins including the actin-related proteins Arp2 and Arp3, regulates the assembly of new actin filament networks at the leading edges of cells. Proteins of the WASP (Wiskott-Aldrich Syndrome protein) family bind directly to the Arp2/3 complex and stimulate its ability to promote the nucleation of new actin filaments. Upstream of WASP-family proteins, receptor tyrosine kinases, the Rho-family GTPase Cdc42, and likely G protein–coupled receptors, receive and transmit the signals leading to WASP-Arp2/3 complex-mediated actin nucleation. Together, these ideas and discoveries suggest complete signaling pathways from outside of the cell to actin polymerization-driven cell motility. While the Arp2/3 complex and WASP family proteins are very important, any model of actin polymerization must include many other participants, in particular Ena/ VASP, gelsolin, and capping protein. Members of the Ena/ VASP family colocalize with the Arp2/3 complex at the leading edges of cells and catalyze the elongation of newly formed filaments. Capping protein and gelsolin regulate the growth of actin filaments by terminating elongation. They also mediate associations between actin and the plasma membrane, and may promote or permit filament elongation under the control of membrane phospholipids.