FAK-independent αvβ3 integrin-EGFR complexes rescue from anoikis matrix-defective fibroblasts

Extracellular matrix (ECM) binding to integrin receptors regulates cell cycle progression and survival. In adherent cells, ECM disassembly induces anoikis, the apoptotic pathway switched on by loss of adhesion. ECM-deficient Ehlers-Danlos syndrome (EDS) fibroblasts, to adhere to rare fibronectin (FN) fibrils, and to proliferate, only organize, as FN receptor, the αvβ3 integrin. We report that in EDS cells the αvβ3 integrin is bound to talin and vinculin, but not to tensin, and that actin cytoskeleton is disorganized. Furthermore, in EDS cells Bcl-2 is down-regulated and caspases are active. We provide evidence that the antibody-mediated αvβ3 integrin or the FN inhibition induces anoikis in EDS cells. The αvβ3 integrin transduces survival signals to pp60src-mediated tyrosine phosphorylated paxillin, instead than to FAK, and interacts with EGF receptor (EGFR). This complex, when activated by EGF and FN, signals for the rescue of EDS cells from anoikis. Therefore, EDS cells, through the αvβ3 integrin-EGFR complexes, engage a paxillin- but not FAK-mediated pathway of cell survival.