FAK-independent alphavbeta3 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 alphavbeta3 integrin. We report that in EDS cells the alphavbeta3 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 alphavbeta3 integrin or the FN inhibition induces anoikis in EDS cells. The alphavbeta3 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 alphavbeta3 integrin-EGFR complexes, engage a paxillin- but not FAK-mediated pathway of cell survival.
Zoppi
Nicoletta
N
Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
Barlati
Sergio
S
Colombi
Marina
M
D000199:Actins / Q000378:metabolism; D023102:Anoikis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004535:Ehlers-Danlos Syndrome / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism; D016608:Talin / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism
D000199:Actins; D005353:Fibronectins; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D051419:Paxillin; D019253:Proto-Oncogene Proteins c-bcl-2; D016608:Talin; D016596:Vinculin; D014443:Tyrosine; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020169:Caspases