Fig. 4

Schematic overview of integrin activation-associated signaling cascades. Integrin activation is regulated by multiple external signals, such as ECM, mechanotransduction or signaling from non-ECM ligands, including growth factor receptors, hormones, and small molecules, which is termed the “outside-in” mechanism. ECM or non-ECM ligand binding and force application results in integrin clustering and initiates downstream signaling to the actin cytoskeleton through recruited talin and vinculin, where actin can simultaneously pull on integrins and further in turn promote force generation. The “outside-in” mechanism then triggers various signaling cascades that ultimately result in cell survival, proliferation, cell spreading, and even tumorigenesis and metastasis. On the plasma membrane, there is also an “inside-out” mechanism, which regulates the displacement of intracellular integrin inhibitors and allows talin or kindlin binding to integrin β-tails, controlling integrin affinity for ECM components. For example, in neutrophils, both Talin-1 and Kindlin-3 are rapidly recruited to activate β2 integrins induced by extracellular chemokines binding to GPCR (G-protein-coupled receptor). Solid arrows indicate activation, the dotted line indicates recruiting, and the solid blunt end arcs indicate inhibitory effects