Integrin Signaling

Abstract

Integrins are heterodimeric transmembrane receptors expressed on virtually all cells in multicellular organisms. They mediate attachment of cells to the extracellular matrix and to other cells. In addition to, and in participation with their adhesive function, integrins are conduits of bidirectional signaling between the extracellular environment and the cell interior. Through outside-in integrin signaling, binding of ligands to integrin extracellular domains initiates intracellular signaling pathways, which regulate processes such as protein phosphorylation, gene expression, proliferation, apoptosis, cell migration, and differentiation. These signals are initiated by conformational changes in the integrin structure propagated from the extracellular head domains, through the transmembrane regions, and terminating at the cytoplasmic tail domains. Conformational changes in the tails subsequently affect the binding and signaling properties of intracellular signaling molecules. Conversely, conformational activation of integrin head domains to promote ligand binding is regulated by intracellular signaling pathways, in a process called ‘inside-out’ integrin signaling. Cytoplasmic proteins associate with integrin tails, leading to allosteric rearrangements in the extracellular head domains to effect a switch from low- to high-affinity ligand binding. This process of inside-out integrin signaling is crucial to hemostasis and the maintenance of normal tissue integrity. Furthermore, ligand binding to integrins can be regulated by avidity modulation by which integrin clustering promotes increased binding to ligands. Thus, intricate regulation of outside-in and inside-out signaling and integrin avidity plays key roles in numerous cellular phenotypes.