Figure 1. Integrin-mediated survival versus apoptotic pathways.

Integrins can paradoxically initiate pro-survival as well as pro-apoptotic signals. Which pathway is more active depends on the ligation status of the surface integrins expressed by a given cell. In a cell in which most of the integrins are ligated, a pro-survival pathway is initiated through increased nuclear factor-κB (NF-κB) or PI3K–AKT activity, decreased p53 activation and increased expression of the pro-survival molecules BCL-2 and FLIP (also known as CFLAR). Cooperative signalling between growth factor receptors and integrins also differentially activates Raf leading to distinct mechanisms of cell survival. Signalling through integrin αvβ3 and the fibroblast growth factor receptor promotes phosphorylation of Ser338 and Ser339 of Raf, protecting cells from the intrinsic pathway of apoptosis, and integrin αvβ5 and vascular endothelial growth factor receptor 2 phosphorylate Tyr340 and Tyr341 of Raf, preventing apoptosis through the extrinsic pathway. In adherent cells in which many of the integrins are unligated, the unligated integrins initiate cleavage of caspase 8, triggering apoptosis through integrin-mediated death (IMD). On complete loss of adhesion, cell death is initiated through a process termed anoikis. Apoptosis induced by anoikis may proceed through either the intrinsic or extrinsic pathways. ECM, extracellular matrix; RTK, receptor tyrosine kinase.