Association of cortactin with dynamic actin

The formation of cell protrusions such as lamellipodia and filopodia in motile cells is dependent on actin polymerization. The actin assembly takes place at the leading edge of the protrusions and is thought to provide the force for forward movement of the plasma membrane (for review see Mitchison and Cramer, 1996). In several cell types the actin meshwork moves in a retrograde manner from the leading edge toward the cell body where actin is then depolymerized (Fisher et al., 1988; Theriot and Mitchison, 1992; Wang, 1985). This movement is known to be myosin dependent (Lin et al., 1996). It has been suggested that attachment of the actin cytoskeleton in lamellipodia to the substrate via transmembrane adhesion receptors stops the retrograde movement and leads to forward movement of the cell body (Lin and Forscher, 1995; Suter et al., 1998). This is supported by the finding that in some very rapidly migrating cell types the actin meshwork in the lamellipodia stays immobile in relation to the substrate (Theriot and Mitchison, 1991). Actin cytoskeleton has also been shown to be crucial for transport of endocytosed molecules. The initial internalization step requires actin cytoskeleton (Lamaze et al., 1997) and the later trafficking of endocytosed molecules is affected by disruption of the actin cytoskeleton (Durrbach et al., 1996). The mechanism by which actin is involved in endosomal trafficking is not well understood. There is also evidence to suggest that endomembrane trafficking and cell motility are somehow connected. Endocytosed molecules are preferentially exocytosed at sites of plasma membrane protrusions (Bretscher and Aguado-Velasco, 1998). Endosomes could transport molecules needed for cell motility to sites of active actin polymerization at the leading edge. Cortactin is a widely expressed actin-binding protein that was originally identified as a substrate for src kinase (Wu et al., 1991). In addition to the actin-binding domain it contains an SH3-domain, several tyrosine phosphorylation sites and a proline-rich region (Wu et al., 1991). It interacts via its SH3domain with several PDZ-family proteins (Du et al., 1998; Katsube et al., 1998; Naisbitt et al., 1999). Cortactin has been implicated in cell motility and in linking transmembrane signaling to the cytoskeleton (Huang et al., 1998; Kinnunen et 4421 Journal of Cell Science 113, 4421-4426 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 JCS1893