Tan Y, Demeter M R, Ruan H, Comb M J
Cell Signaling Technology, Beverly, MA 01915, USA.
J Biol Chem. 2000 Aug 18;275(33):25865-9. doi: 10.1074/jbc.M004199200.
The BH3 domain of BAD mediates its death-promoting activities via heterodimerization to the Bcl-XL family of death regulators. Growth and survival factors inhibit the death-promoting activity of BAD by stimulating phosphorylation at multiple sites including Ser-112 and Ser-136. Phosphorylation at these sites promotes binding of BAD to 14-3-3 proteins, sequestering BAD away from the mitochondrial membrane where it dimerizes with Bcl-XL to exert its killing effects. We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites.
BAD的BH3结构域通过与Bcl-XL家族的死亡调节因子形成异二聚体来介导其促死亡活性。生长和存活因子通过刺激包括Ser-112和Ser-136在内的多个位点的磷酸化来抑制BAD的促死亡活性。这些位点的磷酸化促进BAD与14-3-3蛋白结合，将BAD隔离在线粒体膜之外，在那里它与Bcl-XL形成二聚体以发挥其杀伤作用。我们在此报告，BH3结构域内Ser-155位点的BAD磷酸化是另一种抑制BAD促死亡活性的磷酸化依赖性机制。蛋白激酶A、RSK1和存活因子信号传导刺激BAD在Ser-155位点的磷酸化，阻止BAD与Bcl-XL结合。RSK1使BAD的Ser-112和Ser-155位点均发生磷酸化，并以依赖于两个位点磷酸化的方式挽救BAD介导的细胞死亡。
