Survival Factor-Mediated BAD Phosphorylation Raises the Mitochondrial Threshold for Apoptosis

• Published in: Developmental cell Vol. 3; no. 5; pp. 631 - 643
• Main Authors: Datta, Sandeep Robert, Ranger, Ann M., Lin, Michael Z., Sturgill, James Fitzhugh, Ma, Yong-Chao, Cowan, Chris W., Dikkes, Pieter, Korsmeyer, Stanley J., Greenberg, Michael E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2002
• Subjects: Animals; Apoptosis; B-Lymphocytes - cytology; bcl-Associated Death Protein; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Differentiation; Cell Survival; Cells, Cultured; Cytochrome c Group - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - immunology; Insulin-Like Growth Factor I - pharmacology; Mice; Mice, Inbred C57BL; Mitochondria - metabolism; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Phosphorylation; Platelet-Derived Growth Factor - pharmacology; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal Transduction; T-Lymphocytes - cytology; Thymus Gland - cytology; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/S1534-5807(02)00326-X

Growth factor suppression of apoptosis correlates with the phosphorylation and inactivation of multiple proapoptotic proteins, including the BCL-2 family member BAD. However, the physiological events required for growth factors to block cell death are not well characterized. To assess the contribution of BAD inactivation to cell survival, we generated mice with point mutations in the BAD gene that abolish BAD phosphorylation at specific sites. We show that BAD phosphorylation protects cells from the deleterious effects of apoptotic stimuli and attenuates death pathway signaling by raising the threshold at which mitochondria release cytochrome c to induce cell death. These findings establish a function for endogenous BAD phosphorylation, and elucidate a mechanism by which survival kinases block apoptosis in vivo.