Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex
Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex
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DOI：
10.1074/jbc.m307357200
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发表时间：
2003-11-28
影响因子：
4.8
通讯作者：
Vojtek, AB
中科院分区：
文献类型：
--
作者：
Figueroa, C;Tarras, S;Vojtek, AB
我们证明POSH，JNK信号通路的支架，结合Akt 2。不能结合Akt 2的POSH突变体（POSH W 489 A）表现出与MLK 3的结合增强，并且这种结合的增加伴随着JNK信号传导途径的激活增加。此外，我们表明，MLK 3与POSH的协会增加后，抑制内源性磷脂酰肌醇3-激酶/Akt信号通路。因此，通过POSH组装活性JNK信号传导复合物受到Akt 2的负调控。此外，Akt磷酸化MLK 3的水平在表达POSH的Akt 2结合结构域的细胞中降低，POSH的Akt 2结合结构域充当显性干扰蛋白。综上所述，我们的研究结果支持了一个模型，其中Akt 2结合POSH-MLK-MKK-JNK复合物并磷酸化MLK 3; Akt 2磷酸化MLK 3导致与POSH结合的JNK复合物的分解和JNK信号通路的下调。
We demonstrate that POSH, a scaffold for the JNK signaling pathway, binds to Akt2. A POSH mutant that is unable to bind Akt2 ( POSH W489A) exhibits enhanced-binding to MLK3, and this increase in binding is accompanied by increased activation of the JNK signaling pathway. In addition, we show that the association of MLK3 with POSH is increased upon inhibition of the endogenous phosphatidylinositol 3-kinase/Akt signaling pathway. Thus, the assembly of an active JNK signaling complex by POSH is negatively regulated by Akt2. Further, the level of Akt-phosphorylated MLK3 is reduced in cells expressing the Akt2 binding domain of POSH, which acts as a dominant interfering protein. Taken together, our results support a model in which Akt2 binds to a POSH-MLK-MKK-JNK complex and phosphorylates MLK3; phosphorylation of MLK3 by Akt2 results in the disassembly of the JNK complex bound to POSH and down-regulation of the JNK signaling pathway.