Tiny dancers: the integrin-growth factor nexus in angiogenic signaling

Abstract

A vital step in growth factor-driven angiogenesis is the coordinated engagement of endothelial integrins with the extracellular matrix. The molecular mechanisms that partner growth factors and integrins are being elucidated, revealing an intricate interaction of surface receptors and their signaling pathways.

Figure 1.

Cross-talk between growth factors and integrins in endothelial cells. VEGF binding to VEGFR-2 results in receptor dimerization and phosphorylation of specific tyrosine residues within the intracellular domain of the receptor. PLCγ, Sck, and VRAP (not depicted) all interact directly with VEGFR-2. The mechanism of activation of FAK, Src, MAPK, PI 3-kinase, and AKT by VEGFR-2 is less clearly understood. Recent work indicates that VEGF-mediated Src activation promotes FAK association with αVβ5. The extracellular domain of β3 directs association of αVβ3 with VEGFR-2. Engagement of either VEGFR-2 or αVβ3 enhances the function of the reciprocal receptor. Binding of ECM proteins to αVβ3 triggers phosphorylation of tyrosine residues located in the intracellular domain of the β3 chain and induces receptor clustering. Signaling molecules activated by ligation and/or clustering of αVβ3 include FAK, Src, MAPK, PI 3-kinase, and Rho family members. Recent evidence suggests a role for an unidentified arachidonic acid (AA) metabolite in αVβ3 activation of Rac. Phosphorylation of intracellular tyrosine residues of VEGFR-2 occurs in response to αVβ3 ligation. The p53/bax pathway linked to apoptosis is suppressed by αVβ3 engagement. The proapoptotic mediator caspase 8 may be activated by unligated αVβ3-dependent membrane recruitment. Additionally, ligation of either αVβ3 or αVβ5 may influence the function of the reciprocal receptor.