Erbin inhibits RAF activation by disrupting the Sur-8-Ras-Raf complex
Erbin inhibits RAF activation by disrupting the Sur-8-Ras-Raf complex
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DOI：
10.1074/jbc.m507360200
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发表时间：
2006-01-13
影响因子：
4.8
通讯作者：
Mei, L
中科院分区：
文献类型：
--
作者：
Dai, PG;Xiong, WC;Mei, L
Erbin是富含亮氨酸重复序列（LRR）和PDZ结构域（PDZ domain）家族的成员。它抑制Ras介导的ERK对生长因子的应答激活。在这项研究中，我们研究了Erbin调节Ras-Raf-MEK通路的机制。N-末端LRR结构域是必需的，足以抑制神经调节蛋白激活的ERK激活的报告基因E416-Luc的表达。另一方面，Erbin对Ras激活没有影响，但它减弱了神经调节蛋白诱导的Raf激活，表明Erbin可能通过Ras调节Raf激活。通过LRR结构域，Erbin与Sur-8相互作用，Sur-8是Ras-Raf复合物所必需的支架蛋白。Erbin的表达减弱了Sur-8与活性Ras和Raf的相互作用。此外，Erbin-shRNA，抑制Erbin在mRNA和蛋白质水平的表达，增加的相互作用的Sur-8与Ras和Raf，ERK激活，和神经调节素诱导的内源性乙酰胆碱受体ε亚基mRNA的表达。这些结果表明Erbin在Ras-Raf-MEK途径中的调节作用，表明Erbin可能通过破坏Sur-8-Ras/Raf相互作用来抑制ERK活化。
Erbin is amember of the LAP (leucine-rich repeat (LRR) and PDZ domain) family. It inhibits Ras-mediated activation of ERK in response to growth factors. In this study, we investigated the mechanisms by which Erbin regulates the Ras-Raf-MEK pathway. The N-terminal LRR domain was necessary and sufficient to inhibit neuregulin-activated expression of epsilon 416-Luc, a reporter of ERK activation. On the other hand, Erbin had no effect on Ras activation, but it attenuated neuregulin-induced Raf activation, suggesting that Erbin may regulate Raf activation by Ras. Via the LRR domain, Erbin interacts with Sur-8, a scaffold protein necessary for the Ras-Raf complex. Expression of Erbin attenuated the interaction of Sur-8 with active Ras and Raf. Moreover, Erbin-shRNA, which suppressed Erbin expression at mRNA and protein levels, increased the interaction of Sur-8 with Ras and Raf, ERK activation, and neuregulin-induced expression of endogenous acetylcholine receptor epsilon-subunit mRNA. These results demonstrate a regulatory role of Erbin in the Ras-Raf-MEK pathway, suggesting that Erbin may inhibit ERK activation by disrupting the Sur-8-Ras/Raf interaction.