From membrane to cytoskeleton: enabling a connection.

During development, neurons migrate and undergo extensive morphological changes necessary to establish functional connections. Extracellular cues function through surface receptors to control signaling pathways whose interplay results in the remodeling of the cytoskeleton and thereby changes in cell shape and motility. Past research has identified numerous receptors as important for promoting or directing cell and growth cone movements. Compared with the explosion in information on these surface interactions, however, little is known about the intracellular signaling mechanisms that direct cell motility. Recent work, published in this journal and described in this minireview, has identified a receptor (tyrosine phosphatase, Dlar) and a signaling pathway (Abl kinase) important in regulating axon guidance. These studies provide a provocative link from the cell surface to the actin cytoskeleton through the Ena/VASP family of proteins and Profilin, both of which are known to regulate actin dynamics and are shown in these papers to play important roles in axon growth and guidance. To understand the significance of these papers, it is important to review briefly our current knowledge about regulation of actin dynamics (see Figure 1). Actin filaments form by the polymerization of monomeric ATP-actin, which is followed by slow hydrolysis of the bound ATP to ADP within the filaments. Filament growth is polarized because of a higher affinity of ATP-actin for the “barbed” than for the “pointed” filament end. Figure 1 Selected Interactions between Membrane Receptors and the F-Actin Cytoskeleton Likely to be Important in Neural Development More than 50 proteins have been identified that bind actin and control filament dynamics (reviewed by Mitchison and Cramer, 1996). Some affect monomers by controlling sequestration or nucleotide exchange; others control filament formation and stability by regulating capping, nucleating, cross-linking, bundling, and severing. For example, Profilin, a monomeric globular actin sequestering protein (see Figure 1), is believed to enhance polymerization by catalyzing exchange of ADP for ATP in globular actin, thereby increasing the concentration of polymerizable actin. In some circumstances, though, Profilin may instead inhibit actin polymerization, possibly by sequestering actin monomers. The Arp2/3 complex nucleates filament assembly by stabilizing actin dimers (Figure 1). Arp2/3 also has been shown to bind to the sides of existing filaments, thereby creating branch points in the actin network at the leading edges of migrating cells (Mullins et al., 1998). In contrast, Cofilin binds to ADP regions of filamentous polymerized actin, severing and thereby disassembling filaments. Cellular signaling molecules control actin remodeling by regulating all of these activities. In particular, families of proline-rich proteins, the WASP/SCAR and Ena/VASP families, play crucial roles in actin dynamics, and are believed to act, at least in part, by binding and thereby regulating Profilin’s activity (Figure 1). In addition, the C termini of WASP/SCAR proteins recruit the Arp2/3 complex to nucleate actin filaments (Machesky and Insall, 1998). Integrins and other adhesion molecules may promote actin filament assembly by concentrating Ena/VASP proteins (see Figure 1). The Integrin-associated proteins Zyxin and Vinculin interact with Ena/VASP proteins (Beckerle, 1998). There are other pathways for actin control. Small Rho family GTPases (Cdc42, Rac, and Rho) normally control the formation of cellular actin structures, such as filopodia, lamellipodia, and stress fibers, by regulating the activities of numerous direct and indirect effectors (reviewed by Mackay and Hall, 1998). Receptor tyrosine kinases and serpentine receptors control the activity of these small G proteins through regulation of GDP/GTP exchange factors. Thus, multiple receptors activate signaling pathways that impinge upon actin regulatory elements and thereby remodel the cytoskeleton.