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.
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17 April 2000
Article|
April 17 2000
Integrin-Mediated Survival Signals Regulate the Apoptotic Function of Bax through Its Conformation and Subcellular Localization
Andrew P. Gilmore,
Andrew P. Gilmore
aSchool of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK
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Anthony D. Metcalfe,
Anthony D. Metcalfe
aSchool of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK
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Lewis H. Romer,
Lewis H. Romer
bDepartments of Cell Biology and Anatomy, Pediatrics, and Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
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Charles H. Streuli
Charles H. Streuli
aSchool of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK
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Andrew P. Gilmore
aSchool of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK
Anthony D. Metcalfe
aSchool of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK
Lewis H. Romer
bDepartments of Cell Biology and Anatomy, Pediatrics, and Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
Charles H. Streuli
aSchool of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK
Abbreviations used in this paper: BH, Bcl-2 homology; BrdU, bromodeoxyuridine; DN-FAK, dominant-negative FAK; DSS, disuccinimidyl suberate; ECM, extracellular matrix; PI 3-kinase, phosphatidylinositol 3-kinase; pp125FAK, focal adhesion kinase; polyHEMA, polyhydroxyethylmethacrylate.
Received:
November 15 1999
Revision Requested:
March 06 2000
Accepted:
March 08 2000
Online ISSN: 1540-8140
Print ISSN: 0021-9525
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Cell Biol (2000) 149 (2): 431–446.
Article history
Received:
November 15 1999
Revision Requested:
March 06 2000
Accepted:
March 08 2000
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Citation
Andrew P. Gilmore, Anthony D. Metcalfe, Lewis H. Romer, Charles H. Streuli; Integrin-Mediated Survival Signals Regulate the Apoptotic Function of Bax through Its Conformation and Subcellular Localization. J Cell Biol 17 April 2000; 149 (2): 431–446. doi: https://doi.org/10.1083/jcb.149.2.431
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