Lyons Traci R, Thorburn Jackie, Ryan Philip W, Thorburn Andrew, Anderson Steven M, Kassenbrock C Kenneth
Department of Pathology, the University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
J Biol Chem. 2007 Jul 27;282(30):21987-97. doi: 10.1074/jbc.M704321200. Epub 2007 May 29.
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.
富含SH3结构域蛋白（POSH）与活化的Rac结合，并通过作为支架组装从Rac到JNK激活的信号转导途径来促进细胞凋亡。POSH的过表达在多种细胞类型中诱导细胞凋亡，但通过共表达促生存蛋白激酶Akt可预防细胞凋亡。我们在此报告，POSH在体内和体外都是Akt磷酸化的直接底物，并且我们确定Akt磷酸化的主要位点是POSH的丝氨酸304，其位于Rac结合结构域内。我们进一步表明，POSH的磷酸化导致其结合活化Rac的能力降低，POSH的模拟磷酸化S304D和S304E突变也是如此。S304D突变体POSH诱导细胞凋亡的能力也大大降低。这些发现确定了Akt促进细胞存活的一种新机制。
