Wilhelm Michael, Kukekov Nickolay V, Xu Zhiheng, Greene Lloyd A
Department of Pediatrics, Columbia University Health Sciences, New York, NY 10032, USA.
Dev Neurosci. 2007;29(4-5):355-62. doi: 10.1159/000105476.
The c-Jun N-terminal kinase (JNK) pathway plays an important role in neuronal apoptosis both during normal CNS development and following stroke in adult animals. As with other MAP kinase pathways, scaffold proteins regulate JNK signaling. The scaffold protein POSH (Plenty of SH3s) enhances JNK activation and apoptosis. We identified a POSH homologue, POSH2, which was cloned from rat brain and is present in cortical neurons in vitro. POSH2 mRNA is expressed in a variety of tissues including brain, and this distribution partially overlaps with that of POSH. POSH2 overexpression promotes JNK activation in HEK293 cells and promotes apoptosis in neuronal PC12 cells, which is blocked by a dominant-negative c-Jun. Finally POSH2 contains a functional RING domain and enhances the stability of coexpressed mixed-lineage kinases. These results indicate that POSH2 may regulate JNK activation and consequent apoptosis under conditions of increased expression.
c-Jun氨基末端激酶（JNK）通路在正常中枢神经系统发育过程以及成年动物中风后的神经元凋亡中均发挥重要作用。与其他丝裂原活化蛋白激酶（MAP）通路一样，支架蛋白调节JNK信号传导。支架蛋白POSH（富含SH3结构域蛋白）增强JNK激活及凋亡。我们鉴定出一种POSH同源物POSH2，它是从大鼠脑内克隆出来的，且在体外的皮质神经元中存在。POSH2信使核糖核酸（mRNA）在包括脑在内的多种组织中表达，这种分布与POSH的分布部分重叠。POSH2过表达促进人胚肾293（HEK293）细胞中的JNK激活，并促进神经元PC12细胞中的凋亡，而这种凋亡被显性阴性c-Jun阻断。最后，POSH2含有一个功能性的泛素连接酶环（RING）结构域，并增强共表达的混合谱系激酶的稳定性。这些结果表明，在表达增加的情况下，POSH2可能调节JNK激活及随之而来的凋亡。
