Mechanosensation through integrins: Cells act locally but think globally

Cells sense cues that guide their growth and development by probing their microenvironment with surface membrane receptors that elicit intracellular signals when they bind their ligands. Cell interactions with extracellular matrix (ECM) molecules differ from those with soluble regulatory factors, however, because in addition to ligation-induced signaling, cells also apply traction to their integrin receptors that mediate ECM adhesion (1). Tensional forces generated in the actin cytoskeleton and resisted by the ECM feed back to alter cell shape and function, and different cellular responses are produced depending on the ECM's ability to physically balance this stress. Rigid substrates that support high levels of isometric tension in the cell promote cell spreading and growth in the presence of soluble mitogens, whereas flexible ECM scaffolds that cannot resist cytoskeletal forces promote cell retraction, turn off growth, and switch on differentiation in the same medium (reviewed in ref. 1). Cells also sense local changes in ECM compliance that can influence their rate of migration (2). Tension-dependent changes in cell shape seem to be critical to this process: planar substrates that contain microfabricated ECM islands on the size of single cells can similarly control whether a cell will grow, differentiate, undergo directional motility, or die, depending on their ability to support or restrict cell spreading (3–5). The integrin receptors that mediate this form of mechanical signaling cluster together within spot weld-like anchoring complexes, known as focal adhesions. Molecules that form the structural backbone of the focal adhesion both mechanically couple integrins to the actin cytoskeleton (6, 7) and orient much of the cell's signal transduction machinery (8, 9). When cell-generated forces or external stresses are applied to integrins, a local intracellular transduction response is activated that leads to focal adhesion assembly (10, 11) and associated cytoskeletal strengthening (6, …