POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis
POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis
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DOI：
10.1093/emboj/cdg021
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发表时间：
2003-01-15
期刊：
影响因子：
11.4
通讯作者：
Greene, LA
中科院分区：
文献类型：
--
作者：
Xu, ZH;Kukekov, NV;Greene, LA
我们报道了多域蛋白POSH(大量的SH3)作为JNK神经元死亡途径的支架。该通路由一系列通路组成，包括激活的rac1/cdc42、混合谱系激酶(MLKs)、MAPKs(MKKs)4和7、c-jun氨基末端激酶(JNKs)和c-jun，是包括剥夺神经生长因子(NGF)在内的多种方式诱导神经元死亡所必需的。除了前面描述的与GTP-rac1结合外，我们还发现POSH在体内和体外都能结合MLKs，并与MKKs4、MKKs7和JNKs结合。POSH过表达促进神经细胞的凋亡，这被显性阴性形式的MLKs、MKK4/7和c-jun以及MLK抑制剂所抑制。此外，POSH反义寡核苷酸和POSH小干扰RNA(SiRNA)可抑制NGF戒断诱导的c-jun磷酸化和神经细胞凋亡。因此，POSH似乎在多蛋白复合体中起到了支架的作用，该复合体连接了激活的rac1和JNK凋亡级联的下游元件。
We report that the multidomain protein POSH (plenty of SH3s) acts as a scaffold for the JNK pathway of neuronal death. This pathway consists of a sequential cascade involving activated Rac1/Cdc42, mixed-lineage kinases (MLKs), MAP kinase kinases (MKKs) 4 and 7, c-jun N-terminal kinases (JNKs) and c-jun, and is required for neuronal death induced by various means including nerve growth factor (NGF) deprivation. In addition to binding GTP-Rac1 as described previously, we find that POSH binds MLKs both in vivo and in vitro, and complexes with MKKs 4 and 7 and with JNKs. POSH overexpression promotes apoptotic neuronal death and this is suppressed by dominant-negative forms of MLKs, MKK4/7 and c-jun, and by an MLK inhibitor. Moreover, a POSH antisense oligonucleotide and a POSH small interfering RNA (siRNA) suppress c-jun phosphorylation and neuronal apoptosis induced by NGF withdrawal. Thus, POSH appears to function as a scaffold in a multiprotein complex that links activated Rac1 and downstream elements of the JNK apoptotic cascade.