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首页> 外文期刊>Nature >Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP
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Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP

机译：Ras通过效应蛋白IMP调节有丝分裂信号复合物的组装

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摘要

The signal transduction cascade comprising Raf, mitogen-acti-vated 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 MEK. 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.
机译：包含Raf，促分裂原活化蛋白（MAP）激酶激酶（MEK）和MAP激酶的信号转导级联反应是Ras效应子途径，可介导对环境线索的多种细胞应答，并有助于Ras依赖性致癌转化。在这里我们报告说，Ras效应蛋白通过限制KSR的失活来限制核心酶组分的功能性组装，从而抑制MAP激酶级联对依赖于刺激的激活的敏感性，从而调节MAP激酶级联反应的敏感性。 Raf移至其基材MEK。 IMP是一种Ras反应性E3泛素连接酶，在激活Ras时会被自身多聚泛素化修饰，从而释放出对Raf-MEK复合物形成的抑制作用。因此，Ras通过同时的双重效应子相互作用来激活MAP激酶级联反应：Raf激酶活性的诱导和Raf-MEK复合物形成的抑制。 IMP耗竭导致增加的依赖于刺激的MEK激活，而没有改变反应的时间或持续时间。这些观察结果表明，IMP充当阈值调制器，控制级联对刺激的敏感性，并提供一种机制以允许级联在慢性或复杂信号环境中的适应性行为。

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