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.

A delicate balance of signals regulates cell survival. One set of these signals is derived from integrin-mediated cell adhesion to the extracellular matrix (ECM). Loss of cell attachment to the ECM causes apoptosis, a process known as anoikis. In searching for proteins involved in cell adhesion-dependent regulation of anoikis, we identified Bit1, a mitochondrial protein that is released into the cytoplasm during apoptosis. Cytoplasmic Bit1 forms a complex with AES, a small Groucho/transducin-like enhancer of split (TLE) protein, and induces cell death with characteristics of caspase-independent apoptosis. Cell attachment to fibronectin counteracts the apoptotic effect of Bit1 and AES. Increasing Bit1 expression enhances anoikis, while suppressing the expression reduces it. Thus, we have elucidated an integrin-controlled pathway that is, at least in part, responsible for the cell survival effects of cell-ECM interactions.

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