c-Abl mediates endothelial apoptosis induced by inhibition of integrins αvβ3 and αvβ5 and by disruption of actin

Abstract

Inhibition of integrins IntroductionAngiogenesis and endothelial cell responses are essential processes in diseases, such as cancer, and ischemic conditions. Integrins, heterodimeric cell-surface receptors composed of ␣ and ␤ subunits, are central regulators of angiogenesis and endothelial cell functions. 1 Integrins enable cells to adhere to extracellular matrix (ECM), migrate over ECM substrates, and respond to ECM contact by proliferation, differentiation, and protection from apoptosis mediated by regulation of a number of intracellular signaling pathways. 1-3 Inhibition of integrins ␣v␤3 and ␣v␤5, which are preferentially expressed and activated on angiogenic endothelial cells, induces endothelial apoptosis and impairs tumor angiogenesis. 4,5 ␣v␤3/␣v␤5-integrin signaling is mediated through interactions with an arginine-glycine-aspartic acid (RGD) peptide sequence in matrix proteins, such as vitronectin (VN), and can be abrogated by soluble function-blocking RGD peptides, such as cyclic RGDfV. 4 Indeed, inhibitors of integrin ␣v␤3 are undergoing clinical trials in cancer patients, and cilengitide (EMD 121974; Merck KGaA), an integrin ␣v␤3/␣v␤5 function-blocking RGDfV peptide, has encouraging activity in phase 1 and 2 trials against brain tumors in children and adult cancer patients. 6,7 Integrin ␣v␤3 mechanism of action is complex. ␣v␤3 participates in pathologic angiogenesis, 4,8 supporting its development as a target for therapy. To mediate its function, integrin ␣v␤3 requires activation and phosphorylation of the ␤3 integrin tail on Tyr747 and Tyr459, which signal downstream to pathways involving, among others, Src, FAK, Shc, p53, and p21 WAF . 8,9 Complicating matters, integrin ␣v␤3 cosignals with growth factor receptors, such as vascular endothelial growth factor receptor-2 and others. 8 The intracellular signaling events mediating outside-in and inside-out signaling are complex and depend on the context of activation of the integrin and the cell type studied. Therefore, it is not surprising that the precise molecular mechanisms induced by engagement, crosstalk, or inhibition of ␣v␤3 integrin remain only partially understood.Engagement of integrins with the ECM allows cells to adhere and spread, inducing changes in the actin cytoskeleton. Actin is an abundant cytoskeletal protein important in cell spreading and motility. 10,11 Engagement of integrins with the ECM generates complex bidirectional signaling cascades between integrins and the actin cytoskeleton, which serve to transmit both force and biochemical signals. The interaction of integrins with actin is mostly through a number of intermediary proteins that can be cell-specific and/or stimulus-specific. 11 A critical molecule that interacts with F-actin in fibroblasts is c-Abl. c-Abl integrates multiple signals to coordinate F-actin dynamics, whereas F-actin itself has an inhibitory effect on c-Abl kinase activity. 12-14 Therefore, it is anticipated that actindependent signaling, including that by c-Abl, may mediate at least some of the phenotypes ...

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