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, bu t the molecular mechanisms that link cell surface adhesion events to the in tracellular apoptotic machinery are not understood. Bcl-2 family proteins r egulate apoptosis induced by a variety of cellular insults through acting o n internal membranes. A pro-apoptotic Bcl-2 family protein, Pax, is largely present in the cytosol of many cells, but redistributes to mitochondria af ter treatment with apoptosis-inducing drugs. Using mammary epithelial cells as a model for adhesion-regulated survival, we show that detachment from e xtracellular matrix induced a rapid translocation of Bar to mitochondria co ncurrent with a conformational change resulting in the exposure of its BH3 domain. Bar translocation and BH3 epitope exposure were reversible and occu rred before caspase-activation and apoptosis. Pp125FAK regulated the confor mation of the Bar BH3 epitope, and PI 3-kinase and pp60src prevented apopto sis induced by defective pp125FAK signaling. Our results provide a mechanis tic connection between integrin-mediated adhesion and apoptosis, through th e kinase-regulated subcellular distribution of Bar.