Datta S R, Katsov A, Hu L, Petros A, Fesik S W, Yaffe M B, Greenberg M E
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Mol Cell. 2000 Jul;6(1):41-51.
The Bcl-2 homology 3 (BH3) domain of prodeath Bcl-2 family members mediates their interaction with prosurvival Bcl-2 family members and promotes apoptosis. We report that survival factors trigger the phosphorylation of the proapoptotic Bcl-2 family member BAD at a site (Ser-155) within the BAD BH3 domain. When BAD is bound to prosurvival Bcl-2 family members, BAD Ser-155 phosphorylation requires the prior phosphorylation of Ser-136, which recruits 14-3-3 proteins that then function to increase the accessibility of Ser-155 to survival-promoting kinases. Ser-155 phosphorylation disrupts the binding of BAD to prosurvival Bcl-2 proteins and thereby promotes cell survival. These findings define a mechanism by which survival signals inactivate a proapoptotic Bcl-2 family member, and suggest a role for 14-3-3 proteins as cofactors that regulate sequential protein phosphorylation events.
促凋亡Bcl-2家族成员的Bcl-2同源结构域3（BH3）介导其与抗凋亡Bcl-2家族成员的相互作用并促进细胞凋亡。我们报告称，生存因子可触发促凋亡Bcl-2家族成员BAD在BAD BH3结构域内的一个位点（Ser-155）发生磷酸化。当BAD与抗凋亡Bcl-2家族成员结合时，BAD Ser-155的磷酸化需要Ser-136先发生磷酸化，Ser-136的磷酸化会募集14-3-3蛋白，这些蛋白随后发挥作用，增加Ser-155对促进生存激酶的可及性。Ser-155的磷酸化会破坏BAD与抗凋亡Bcl-2蛋白的结合，从而促进细胞存活。这些发现确定了一种生存信号使促凋亡Bcl-2家族成员失活的机制，并提示14-3-3蛋白作为辅助因子在调节连续蛋白磷酸化事件中发挥作用。
