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Kinase Suppressor of Ras Forms a Multiprotein Signaling Complex and Modulates MEK Localization

机译：Ras的激酶抑制剂形成一种多蛋白信号复合物，并调节MEK的定位。

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Genetic screens for modifiers of activated Ras phenotypes have identified a novel protein, kinase suppressor of Ras (KSR), which shares significant sequence homology with Raf family protein kinases. Studies using Drosophila melanogaster andCaenorhabditis elegans predict that KSR positively regulates Ras signaling; however, the function of mammalian KSR is not well understood. We show here that two predicted kinase-dead mutants of KSR retain the ability to complement ksr-1 loss-of-function alleles in C. elegans, suggesting that KSR may have physiological, kinase-independent functions. Furthermore, we observe that murine KSR forms a multimolecular signaling complex in human embryonic kidney 293T cells composed of HSP90, HSP70, HSP68, p50CDC37, MEK1, MEK2, 14-3-3, and several other, unidentified proteins. Treatment of cells with geldanamycin, an inhibitor of HSP90, decreases the half-life of KSR, suggesting that HSPs may serve to stabilize KSR. Both nematode and mammalian KSRs are capable of binding to MEKs, and three-point mutants of KSR, corresponding to C. elegans loss-of-function alleles, are specifically compromised in MEK binding. KSR did not alter MEK activity or activation. However, KSR-MEK binding shifts the apparent molecular mass of MEK from 44 to >700 kDa, and this results in the appearance of MEK in membrane-associated fractions. Together, these results suggest that KSR may act as a scaffolding protein for the Ras-mitogen-activated protein kinase pathway.
机译：活化Ras表型修饰子的遗传筛选已鉴定出一种新型蛋白质，即Ras激酶抑制剂（KSR），该蛋白与Raf家族蛋白激酶具有明显的序列同源性。使用果蝇（Drosophila melanogaster）和秀丽线虫（Caenorhabditis elegans）的研究表明，KSR积极调控Ras信号传导。然而，哺乳动物KSR的功能尚不十分清楚。我们在这里显示，两个预测的KSR激酶死亡突变体保留了补充 C中 ksr-1 功能丧失等位基因的能力。线虫，表明KSR可能具有不依赖激酶的生理功能。此外，我们观察到鼠KSR在人类胚胎肾293T细胞中形成了多分子信号复合物，该细胞由HSP90，HSP70，HSP68，p50 CDC37 ，MEK1，MEK2、14-3-3等组成，未鉴定的蛋白质。用格尔德霉素（一种HSP90抑制剂）处理细胞会降低KSR的半衰期，表明HSP可能有助于稳定KSR。线虫和哺乳动物的KSR都能够结合MEK和KSR的三点突变体，对应于 C。秀丽隐杆线虫功能丧失的等位基因在MEK结合中特别受到损害。 KSR不会改变MEK的活性或激活。但是，KSR-MEK结合将MEK的表观分子量从44 kDa转变为> 700 kDa，这导致膜相关部分中出现MEK。总之，这些结果表明，KSR可能充当Ras促丝分裂原激活的蛋白激酶途径的支架蛋白。

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