Although there has been tremendous progress towards defining signaling pathways that trigger cell death, an understanding of the mechanisms by which growth factor suppress death and promote survival has remained elusive. Our laboratory has defined a pathway by growth factors interact with the cellular death machinery to inhibit its function. We have identified a protein kinase cascade, the BCL-2 family member, BAD. Once phosphorylated BAD is translocated within the cell so that it promotes survival rather than death. We have found that when over-expressed in neurons BAD triggers cell death unless it is phosphorylated at a specific site, Serine-136, by the Serine/Threonine kinase Akt. It is not yet clear how the phosphorylation of BAD promotes cell survival but that when phosphorylated plays an important role in cell survival. We propose a series of experiments that will: 1) determine if endogenous BAD is phosphorylated at Ser-136 and if this phosphorylation event is mediated by the PI3K/Akt signaling pathway and/or other signaling pathways 2) characterize the protein phosphorylation at Ser-136 inhibits BAD's apoptotic function. 3) investigate the mechanism by which the phosphorylation of BAD inactivates BAD's apoptotic function. 3) investigate the mechanism by which the phosphorylation of BAD inactivates BAD's apoptotic function and stimulates it survival function, 4) characterize the biochemical and biological properties of three novel mammalian BAD homologues that we have recently identified. The characterization of the mechanisms by which Akt and BAD family members regulate cell survival and apoptosis may provide insight into how the disruption of normal survival and apoptotic mechanisms leads to cell degeneration or oncogenesis. As these cellular pathways become better defined it may be possible to treat genetically based, or environmentally induced degenerative disorders or cancers, through the development of small molecule therapeutics that selectively potentiate a component(s) of the survival or death promoting signaling pathways
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