The RhoGEF GEF-H1 Is Required for Oncogenic RAS Signaling via KSR-1
The RhoGEF GEF-H1 Is Required for Oncogenic RAS Signaling via KSR-1
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DOI：
10.1016/j.ccr.2014.01.025
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发表时间：
2014-02-10
期刊：
影响因子：
50.3
通讯作者：
Rottapel, Robert
中科院分区：
文献类型：
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作者：
Cullis, Jane;Meiri, David;Rottapel, Robert
致癌RAS的细胞转化在支架蛋白KSR-1的严格调控下参与MAPK通路。在这里，我们报告说，鸟嘌呤核苷酸交换因子GEF-H1在RAS/MAPK通路的正反馈回路中起着至关重要的作用，独立于其RhoGEF活性。GEF-H1作为连接PP 2A B'亚基与KSR-1的接头蛋白，从而介导KSR-1 S392的去磷酸化和MAPK信号传导的活化。GEF-H1对于HRAS（V12）转化细胞和胰腺肿瘤异种移植物的生长和存活是重要的。GEF-H1表达由致癌RAS诱导，并与胰腺肿瘤进展相关。因此，我们的研究结果，确定GEF-H1作为MAPK信号的放大器，并提供RAS突变肿瘤的进展机制的见解。
Cellular transformation by oncogenic RAS engages the MAPK pathway under strict regulation by the scaffold protein KSR-1. Here, we report that the guanine nucleotide exchange factor GEF-H1 plays a critical role in a positive feedback loop for the RAS/MAPK pathway independent of its RhoGEF activity. GEF-H1 acts as an adaptor protein linking the PP2A B' subunits to KSR-1, thereby mediating the dephosphorylation of KSR-1 S392 and activation of MAPK signaling. GEF-H1 is important for the growth and survival of HRAS(V12)-transformed cells and pancreatic tumor xenografts. GEF-H1 expression is induced by oncogenic RAS and is correlated with pancreatic neoplastic progression. Our results, therefore, identify GEF-H1 as an amplifier of MAPK signaling and provide mechanistic insight into the progression of RAS mutant tumors.