Erbin suppresses the MAP kinase pathway
Erbin suppresses the MAP kinase pathway
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DOI：
10.1074/jbc.m205413200
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发表时间：
2003-01-10
影响因子：
4.8
通讯作者：
Mei, L
中科院分区：
文献类型：
--
作者：
Huang, YZ;Zang, MW;Mei, L
我们在这里提出的证据表明，Erbin是一个负调控的Ras-Raf-Erk信号通路。Erbin的表达降低了AChR E亚基基因的转录，这是一个由Erk激活介导的事件。虽然Erbin通过PDZ结构域与ErbB 2 C末端相互作用，但Erbin对ErbB 2酪氨酸磷酸化或与衔接蛋白She和Grb 2的结合没有影响。与此相反，Erbin的表达大大削弱了Erk的激活，但不是Akt，通过配体激活受体酪氨酸激酶。此外，Erbin抑制活性Ras对Erk的激活，而在活性Raf-1存在下则不能。Erbin与活性Ras结合，但不与非活性Ras或Raf结合。因此，Erbin在体内和体外均干扰Ras和Raf之间的相互作用。最后，Erbin的过表达导致抑制NGF诱导的PC 12细胞的神经元分化，而特异性siRNA下调内源性Erbin则表现出相反的效果。总的来说，我们的研究已经确定Erbin作为一种新的抑制Ras信号通过破坏Ras-Raf相互作用。
We present evidence here that Erbin is a negative regulator of the Ras-Raf-Erk signaling pathway. Expression of Erbin decreases transcription of the AChR E-subunit gene, an event that is mediated by Erk activation. Although it interacts with the ErbB2 C terminus through the PDZ domain, Erbin has no effect on ErbB2 tyrosine phosphorylation or binding to the adaptor proteins She and Grb2. In contrast, expression of Erbin greatly impairs activation of Erk, but not Akt, by ligands that activate receptor tyrosine kinases. Moreover, Erbin inhibits the Erk activation by active Ras, while it fails to do so in the presence of active Raf-1. Erbin associates with active Ras, but not inactive Ras nor Raf. Consistently, Erbin interferes with the interaction between Ras and Raf both in vivo and in vitro. Finally, overexpression of Erbin leads to inhibition of NGF-induced neuronal differentiation of PC12 cells, whereas down-regulation of endogenous Erbin by specific siRNA exhibits an opposite effect. Collectively, our study has identified Erbin as a novel suppressor of the Ras signaling by disrupting the Ras-Raf interaction.