KSR modulates signal propagation within the MAPK cascade
KSR modulates signal propagation within the MAPK cascade
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DOI：
10.1101/gad.10.21.2684
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发表时间：
1996-11-01
影响因子：
10.5
通讯作者：
Morrison, DK
中科院分区：
文献类型：
--
作者：
Therrien, M;Michaud, NR;Morrison, DK
Ras激酶抑制因子（KSR）是Ras依赖性信号通路的一个重要组成部分。在这份报告中，我们表明，小鼠KSR 1（mKSR 1）与激活Ras合作，以促进非洲爪蟾卵母细胞成熟和细胞转化，并提供证据表明，这种合作是通过加速有丝分裂原和细胞外调节激酶（MEK）和有丝分裂原活化蛋白激酶（MAPK）激活。我们还发现，mKSR 1协会与Raf-1在质膜Ras依赖性的方式，表明膜结合激酶信号复合物的存在。虽然mKSR 1在结构上与Raf-1相关，但我们的研究结果揭示了这些蛋白质之间惊人的功能差异。与Raf-1的分离的氨基和羧基末端结构域形成鲜明对比，KSR氨基末端也与Ras合作，而羧基末端激酶结构域阻断pas信号传导以及MEK和MAPK活化。分离的KSR激酶结构域抑制非洲爪蟾卵母细胞成熟，细胞转化，和果蝇眼睛的发展，这表明分离的氨基和羧基末端结构域已解耦的正常调节KSR作为一个积极的效应Ras信号。总之，我们的研究结果表明，mKSR 1是MAPK模块的一个组成部分，通过一种新的机制来调节Raf-1，MEK 1和MAPK之间的信号传播。
Kinase suppressor of Ras (KSR) is a recently identified component of Ras-dependent signaling pathways. In this report, we show that murine KSR1 (mKSR1) cooperates with activated Ras to promote Xenopus oocyte maturation and cellular transformation and provide evidence that this cooperation occurs by accelerating mitogen and extracellular regulated kinase (MEK) and mitogen-activated protein kinase (MAPK) activation. We also find that mKSR1 associates with Raf-1 at the plasma membrane in a Ras-dependent manner, indicating the presence of a membrane-bound kinase signaling complex. Although mKSR1 is related structurally to Raf-1, our findings reveal striking functional differences between these proteins. In marked contrast to the isolated amino- and carboxy-terminal domains of Raf-1, the KSR amino terminus also cooperates with Ras, whereas the carboxy-terminal kinase domain blocks pas signaling as well as MEK and MAPK activation. The isolated KSR kinase domain suppressed Xenopus oocyte maturation, cellular transformation, and Drosophila eye development, suggesting that separation of the amino- and carboxy-terminal domains has uncoupled the normal regulation of KSR as a positive effector of Ras signaling. Together, our findings indicate that mKSR1 is an integral component of the MAPK module functioning via a novel mechanism to modulate signal propagation between Raf-1, MEK1, and MAPK.