Platelet-derived Growth Factor Receptor β and Vascular Endothelial Growth Factor Receptor 2 Bind to the β3Integrin through Its Extracellular Domain

Abstract

Integrin-mediated cell attachment and growth factor stimulation often act synergistically on cell proliferation, differentiation, migration, and survival. Some of these synergistic effects depend on the physical interaction of integrins with growth factor receptors. Here we examine the nature of the physical interaction between the ␣ v ␤ 3 integrin and two receptor tyrosine kinases (RTKs), the platelet-derived growth factor receptor ␤ (PDGF-R␤) and the vascular endothelial growth factor receptor 2 (VEGF-R2, also known as KDR and flk-1). Both of these RTKs associate with the ␣ v ␤ 3 integrin but do not associate with ␤ 1 integrins. Furthermore, growth factor stimulation of these RTKs promotes increased cell proliferation and migration when cells are attached to the ␣ v ␤ 3 ligand, vitronectin. We show that ␣ v ␤ 3 in which the ␤ 3 cytoplasmic domain is deleted or replaced with the ␤ 1 cytoplasmic domain coimmunoprecipitates with PDGF-R␤ and VEGF-R2. The ␤ 3 extracellular domain alone was sufficient for the PDGF-R␤ association whereas the VEGF-R2 association required the presence of the ␣ v subunit. Activation of the RTKs by their ligands was not required for them to associate with the integrin. Cell migration to PDGF was enhanced in the cells transfected with the chimeric subunit containing the ␤ 3 extracellular domain but not when that domain came from the ␤ 1 subunit. These results show that the interactions that lead to the association of the ␣ v ␤ 3 integrin with PDGF-R␤ and VEGF-R2 and enhancement of RTK activity take place outside the cell.

Improved growth factor directed vascularization into fibrin constructs through inclusion of additional extracellular molecules

“…Growth factor receptor-integrin interactions have been shown to modulate cellular responses to growth factors (Borges et al, 2000;Doerr and Jones, 1996;Guo et al, 2001;Jikko et al, 1999). Therefore, unique ECM compositions may modulate cellular responses to the same growth factor.…”

“…Therefore, unique ECM compositions may modulate cellular responses to the same growth factor. One reason for this modulation may be that both integrin and growth factor signaling utilize many of the same intracellular proteins (Borges et al, 2000). This interaction may also arise from the bridging of growth factor receptors and integrins via ECM molecules that contain integrin binding sites and bound growth factor (Fontana et al, 2005).…”

Integrins as a distinct subtype of dependence receptors

“…10 Interestingly, nonmigratory cells exposed to the growth factors present in tissue culture medium appear to undergo continuous rearrangement of focal adhesions, despite remaining in place. 52 Since the receptors for these growth factors have been shown to physically associate with integrins, 53,54 it is tempting to speculate that integrins may function as 'coreceptors' for these growth factors. Ironically then, these growth factor receptors, which have been suggested to function via 'classic' on/off signaling mechanisms, are actually integrin-dependent.…”

“…For example, integrin avb3 has been described to associate laterally with VEGF receptor 2 in endothelial cells. 53 Nevertheless, endothelial cells express at least eight different integrin heterodimers, 16 and antagonists of integrin avb3 do not influence cell attachment to ligands of other integrins present on the cell. Collagen is bound principally by integrin a2b1 in endothelial cells.…”

Integrins: A flexible platform for endothelial vascular tyrosine kinase receptors

“…Once engaged with vitronection or fibrin, this integrin participates in a complex containing VEGFR-2 and PI 3-kinase [6][7][8]. The impact of the integrin pair on this complex is illustrated by studies performed with an anti-β 3 antibody that interferes with αvβ3 clustering but not with cell adhesion to the ECM.…”