Integrin-mediated survival signals regulate the apoptotic function of Bax through its conformation and subcellular localization.
Most normal cells require adhesion to extracellular matrix for survival, but the molecular mechanisms that link cell surface adhesion events to the intracellular apoptotic machinery are not understood. Bcl-2 family proteins regulate apoptosis induced by a variety of cellular insults through acting on internal membranes. A pro-apoptotic Bcl-2 family protein, Bax, is largely present in the cytosol of many cells, but redistributes to mitochondria after treatment with apoptosis-inducing drugs. Using mammary epithelial cells as a model for adhesion-regulated survival, we show that detachment from extracellular matrix induced a rapid translocation of Bax to mitochondria concurrent with a conformational change resulting in the exposure of its BH3 domain. Bax translocation and BH3 epitope exposure were reversible and occurred before caspase activation and apoptosis. Pp125FAK regulated the conformation of the Bax BH3 epitope, and PI 3-kinase and pp60src prevented apoptosis induced by defective pp125FAK signaling. Our results provide a mechanistic connection between integrin-mediated adhesion and apoptosis, through the kinase-regulated subcellular distribution of Bax.
Gilmore
A P
AP
School of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK.
Metcalfe
A D
AD
Romer
L H
LH
Streuli
C H
CH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016023:Integrins / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D008813:Mice, Inbred ICR; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011102:Polyhydroxyethyl Methacrylate / Q000494:pharmacology; D011247:Pregnancy; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D014162:Transfection; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D004791:Enzyme Inhibitors; D016023:Integrins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D011102:Polyhydroxyethyl Methacrylate; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); C496051:Ptk2 protein, mouse