Regulation of the pro-apoptotic scaffolding protein POSH by Akt
Regulation of the pro-apoptotic scaffolding protein POSH by Akt
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DOI：
10.1074/jbc.m704321200
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发表时间：
2007-07-27
影响因子：
4.8
通讯作者：
Kassenbrock, C. Kenneth
中科院分区：
文献类型：
--
作者：
Lyons, Traci R.;Thorburn, Jackie;Kassenbrock, C. Kenneth
Posh(大量的SH3结构域)与激活的RAC结合，通过作为支架组装从RAC到JNK激活的信号转导通路，促进细胞凋亡。过表达POSH可诱导多种细胞类型的凋亡，但通过共表达促生存蛋白激酶Akt可以防止细胞凋亡。我们在这里报道了POSH是Akt在体内和体外磷酸化的直接底物，我们确定Akt磷酸化的一个主要部位是POSH的丝氨酸304，它位于RAC结合结构域。我们进一步表明，POSH的磷酸化导致与激活的RAC结合的能力降低，POSH的拟磷酸化S304D和S304E突变也是如此。S304D突变体POSH诱导细胞凋亡的能力也显著降低。这些发现确定了Akt促进细胞存活的新机制。
POSH (Plenty of SH3 domains) binds to activated Rac and promotes apoptosis by acting as a scaffold to assemble a signal transduction pathway leading from Rac to JNK activation. Overexpression of POSH induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase Akt. We report here that POSH is a direct substrate for phosphorylation by Akt in vivo and in vitro, and we identify a major site of Akt phosphorylation as serine 304 of POSH, which lies within the Rac-binding domain. We further show that phosphorylation of POSH results in a decreased ability to bind activated Rac, as does phosphomimetic S304D and S304E mutation of POSH. S304D mutant POSH also shows a strongly reduced ability to induce apoptosis. These findings identify a novel mechanism by which Akt promotes cell survival.