Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis

Abstract

The cross-talk between receptor tyrosine kinases and integrin receptors are known to be crucial for a number of cellular functions. On endothelial cells, an interaction between integrin alphavbeta3 and VEGFR2 seems to be particularly important process during vascularization. Importantly, the functional association between VEGFR2 and integrin alphavbeta3 is of reciprocal nature since each receptor is able to promote activation of its counterpart. This mutually beneficial relationship regulates a number of cellular activities involved in angiogenesis, including endothelial cell migration, survival and tube formation, and hematopoietic cell functions within vasculature. This article discusses several possible mechanisms reported by different labs which mediate formation of the complex between VEGFR-2 and alphavbeta3 on endothelial cells. The pathological consequences and regulatory events involved in this receptor cross-talk are also presented.

Fig. 1

a The cartoon depicts four possible mechanisms responsible for the complex formation between VEGFR2 and α_Vβ₃ on the surface of endothelial cells and the functional consequences of this cross-talk. Activation-induced complex was demonstrated in [48, 55], direct binding of extracellular domains was shown in [47], cross linking by transglutaminases was demonstrated in [87], possible coupling by the common ligands suggested based on [92]. Physiological and pathological consequences of the interplay between these two receptors are discussed in [35, 46, 56]. b The diagram shows possible sequence of molecular events involved in interaction between VEGFR2 and α_Vβ₃. As discussed in the text, the process is likely to be initiated by activation of VEGFR2 by VEGF, possibly, by intracellular-autocrine loop. It followed by the recruitment of c-src to phosphorylated VEGFR2 together with activation of a number of other signaling molecules. C-Src phosphorylates cytoplasmic domain of α_Vβ₃ and in concert with other kinases (e.g. PI3K pathway) promote activation of this integrin, which, in turn, ultimately results in its conformational changes and increase in ligand binding affinity. Ligation of integrin triggers outside-in signaling which further augments cell activation