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© The Rockefeller University Press, 0021-9525/2000//431 $5.00
The Journal of Cell Biology, Volume 149, Number 2, , 2000 431-446

Integrin-Mediated Survival Signals Regulate the Apoptotic Function of Bax through Its Conformation and Subcellular Localization

^a School of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK
^b Departments of Cell Biology and Anatomy, Pediatrics, and Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
School of Biological Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester M13 9PT, UK.+44 161 275 7700+44 161 275 5576

cstreuli{at}man.ac.uk

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.

Key Words: apoptosis • Bax • mammary • adhesion • pp125FAK

© 2000 The Rockefeller University Press

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