Cell adhesion: integrating cytoskeletal dynamics and cellular tension

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Abstract
Cell migration affects all morphogenetic processes and contributes to numerous diseases, including cancer and cardiovascular disease. Cell migration begins with protrusion of the cell membrane, followed by the formation of new adhesions at the cell front that link the actin cytoskeleton to the substratum, generation of traction forces that move the cell forwards and disassembly of adhesions at the cell rear. Cells exhibit a continuum of migration modes that are determined by several factors, among the most important being substrate compliance and the intrinsic contractility of the cells. The steps in the migration cycle — assembly, maturation and disassembly — are tightly coupled to actin polymerization and organization, and actin–myosin contraction, which are in turn regulated by Rho GTPases and protein Tyr kinases. Adhesion dynamics are regulated by complex feedback loops with Rho proteins and a poorly understood reciprocity between Rac and Rho activation that is mediated through the action of guanine nucleotide exchange factors and GTPase-activating proteins. Adhesions provide cells with the ability to sense the mechanical properties of the substratum and subsequently modulate myosin II activity, integrin clustering, adhesion size and composition, and downstream signalling. It is likely that myosin II is regulated by changes in integrin signalling mediated by a feedback loop that connects adhesion, contractility and signalling through Rho GTPases.