Integrins and extracellular matrix in mechanotransduction

Abstract

Integrins bind extracellular matrix fibrils and associate with intracellular actin filaments through a variety of cytoskeletal linker proteins to mechanically connect intracellular and extracellular structures. Each component of the linkage from the cytoskeleton through the integrin-mediated adhesions to the extracellular matrix therefore transmits forces that may derive from both intracellular, myosin-generated contractile forces and forces from outside the cell. These forces activate a wide range of signaling pathways and genetic programs to control cell survival, fate, and behavior. Additionally, cells sense the physical properties of their surrounding environment through forces exerted on integrin-mediated adhesions. This article first summarizes current knowledge about regulation of cell function by mechanical forces acting through integrin-mediated adhesions and then discusses models for mechanotransduction and sensing of environmental forces.

Figure 1.

A model for stiffness sensing. (A) The lamellipodial edge has actin that is moving backward because of a combination of the force from polymerization pushing against the plasma membrane and pulling force from myosin further back in the cell. Integrins are bound to fibronectin or other ECM proteins adsorbed to the substrate or incorporated into the insoluble matrix, and connect to the actin through linker proteins such as talin and vinculin. (B) Binding of the linker to the actin triggers a rapid increase in tension and, assuming slip bond behavior, dissociation of the linkage (C). (D–E) On a soft substrate, tension is applied in the same way but deformation of the substrate allows the fibronectin and integrin to move backward too. Thus, force build-up slows and the interaction is prolonged. One can propose variations on this theme. For example, if linkages are catch bonds, on soft substrata, the slow onset of tension may lead to a shorter lifetime for the bound state. The central idea is that the clutch mechanism allows the stiffness of the substratum to control the timing of the protein-protein interactions, which can lead to changes in signaling.