Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP
Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP
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DOI：
10.1038/nature02237
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发表时间：
2004-01-15
期刊：
影响因子：
64.8
通讯作者：
White, MA
中科院分区：
文献类型：
--
作者：
Matheny, SA;Chen, CY;White, MA
由Raf、丝裂原活化蛋白(MAP)激酶(MEK)和MAP激酶组成的信号转导通路是一条RAS效应通路，介导细胞对环境信号的不同反应，参与RAS依赖的致癌转化。在这里，我们报道了RAS效应蛋白通过KSR的失活来限制核心酶组分的功能组装，从而阻止有丝分裂信号传播(IMP)调节MAP激酶级联反应对刺激依赖的激活的敏感性。KSR是一种将激活的Raf偶联到其底物MEK1上的支架/接头蛋白。IMP是一种RAS反应的E3泛素连接酶，当RAS被激活时，它被自身多泛素化修饰，从而释放对Raf-MEK复合体形成的抑制。因此，RAS通过同时的双重效应相互作用激活MAPK级联反应：诱导Raf激酶活性和抑制Raf-MEK复合体的形成。IMP耗竭导致依赖刺激的MEK激活增加，而不改变反应的时间或持续时间。这些观察表明，IMP起到阈值调制器的作用，控制级联反应对刺激的敏感性，并提供一种机制，允许级联反应在慢性或复杂的信号环境中的适应行为。
The signal transduction cascade comprising Raf, mitogen-activated protein (MAP) kinase kinase (MEK) and MAP kinase is a Ras effector pathway that mediates diverse cellular responses to environmental cues and contributes to Ras-dependent oncogenic transformation. Here we report that the Ras effector protein Impedes Mitogenic signal Propagation (IMP) modulates sensitivity of the MAP kinase cascade to stimulus-dependent activation by limiting functional assembly of the core enzymatic components through the inactivation of KSR, a scaffold/adaptor protein that couples activated Raf to its substrate MEK1. IMP is a Ras-responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination, which releases the inhibition of Raf-MEK complex formation. Thus, Ras activates the MAP kinase cascade through simultaneous dual effector interactions: induction of Raf kinase activity and derepression of Raf-MEK complex formation. IMP depletion results in increased stimulus-dependent MEK activation without alterations in the timing or duration of the response. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus and providing a mechanism to allow adaptive behaviour of the cascade in chronic or complex signalling environments.