Cytoskeleton cross‐talk during cell motility

Abstract

Cell crawling entails the coordinated creation and turnover of substrate contact sites that interface with the actin cytoskeleton. The initiation and maturation of contact sites involves signalling via the Rho family of small G proteins, whereas their turnover is under the additional influence of the microtubule cytoskeleton. By exerting relaxing effects on substrate contact assemblies in a site-and dose-specific manner, microtubules can promote both protrusion at the front and retraction at the rear, and thereby control cell polarity. z 1999 Federation of European Biochemical Societies. 1. Cytoskeleton-contact interplay Of the three polymers that make up the cytoskeleton, it is the ¢laments of the actin cytoskeleton that underlie the cell membrane and that contribute directly to the maintenance of cell shape and form. Intermediate ¢laments are dispensable for cell shape determination since in their absence cells can di¡erentiate normally [1], whereas microtubules have an important , but indirect in£uence on cell shape, a topic to which we will return below. Much of what we now know about the mechanisms controlling the organisation of the actin cytoskeleton comes from studies of ¢broblastic cells in culture. Two general aspects may ¢rst be highlighted: (1) the dynamic nature of the actin cytoskeleton; and (2) the variety of assemblies of actin ¢la-ments that can be generated in vivo. Among these actin assemblies (reviewed in [2]), the most ubiquitous are the prominent bundles of actin ¢laments that make up thèstress ¢bres' and thèlamellipodia' and`¢lopodiaand`¢lopodia' that form at the cell periphery. The organisation of each of these assemblies is stabilised by speci¢c sets of actin-associated proteins, conferring on them di¡erent functions. Stress ¢bres are contractile and serve to develop strong substrate anchorage, whereas la-mellipodia and ¢lopodia are required for spreading and mo-tility. Central players in signalling the formation of these actin ¢lament arrays are the members of the Rho family of small GTPases: Rho, Rac and Cdc42; Rho activity is required for stress ¢bre formation and Rac and Cdc42 for lamellipodia and ¢lopodia, respectively [3]. To what extent each of these actin ¢lament assemblies is expressed in a cell is largely determined by the cell type and the nature of the substrate on which it is induced to spread, illustrating a feedback between Rho family regulation and the response to extracellular matrix [4,5]. It is now well established that the attachment of a cell to a substrate does not occur uniformly over its ventral surface, but at speci¢c, focal-ised sites of adhesion. At these sites, transmembrane matrix receptors (integrins) link matrix ligands on the outside of the cell with the actin cytoskeleton on the inside [6]. Notably, it is the dynamic interplay between the formation and turnover of contact sites and the simultaneous generation and re-organisation of the actin cytoskeleton that determines the form and motile behaviour of a cell. Signi¢cant in this connection is the existenc...

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