14-3-3 inhibits bad-induced cell death through interaction with serine-136
14-3-3 inhibits bad-induced cell death through interaction with serine-136
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DOI：
10.1124/mol.60.6.1325
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发表时间：
2001-12-01
影响因子：
3.6
通讯作者：
Fu, H
中科院分区：
文献类型：
--
作者：
Masters, SC;Yang, HZ;Fu, H
14-3-3蛋白是一个多功能磷酸丝氨酸结合分子家族，可以作为生存信号的效应子。了解14-3-3的促生存作用的分子基础可能会导致开发可用于治疗涉及凋亡失调的疾病的药物。14-3-3的一个靶点是促凋亡Bcl-2家族成员Bad。Bad的丝氨酸磷酸化与14-3-3结合和抑制Bad诱导的细胞死亡相关，但三个已知磷酸化位点对14-3-3结合的相对贡献尚未确定。在这里，我们证明了Bad的S136对于14-3-3相互作用是至关重要的，但是S112似乎是不重要的。14-3-3/Bad相互作用严格依赖于体外、酵母和哺乳动物细胞中磷酸化S136的存在。而S112突变对14-3-3结合无影响。野生型和S112 A Bad引起的死亡，而不是S136 A Bad引起的死亡，可以通过14-3-3几乎完全消除。这些数据支持14-3-3在调节Bad促凋亡活性中的关键作用。14-3-3对Bad的作用主要由S136的磷酸化控制，而S112可能代表了一个14-3-3-独立的途径。
14-3-3 proteins are a family of multifunctional phosphoserine binding molecules that can serve as effectors of survival signaling. Understanding the molecular basis for the prosurvival effect of 14-3-3 may lead to the development of agents useful in the treatment of disorders involving dysregulated apoptosis. One target of 14-3-3 is the proapoptotic Bcl-2 family member Bad. Serine phosphorylation of Bad is associated with 14-3-3 binding and inhibition of Bad-induced cell death, but the relative contributions of the three known phosphorylation sites to 14-3-3 binding have not been established. Here we demonstrate that S136 of Bad is vital for 14-3-3 interaction, but S112 seems to be dispensable. 14-3-3/Bad interaction was strictly dependent on the presence of phosphorylated S136 in vitro, in yeast, and in mammalian cells. However, mutation of S112 did not affect 14-3-3 binding. The death caused by wild-type and S112A Bad, but not that caused by S136A Bad, could be almost completely abrogated by 14-3-3. These data support a critical role for 14-3-3 in regulating Bad proapoptotic activity. The effect of 14-3-3 on Bad is controlled largely by phosphorylation of S136, whereas S112 may represent a 14-3-3-independent pathway.