KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals.
KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals.
复制标题
DOI：
10.1016/j.molcel.2009.06.001
复制
发表时间：
2009-06-26
期刊：
影响因子：
16
通讯作者：
Morrison, Deborah K.
中科院分区：
文献类型：
--
作者：
Dougherty, Michele K.;Ritt, Daniel A.;Zhou, Ming;Specht, Suzanne I.;Monson, Daniel M.;Veenstra, Timothy D.;Morrison, Deborah K.
蛋白质支架已成为MAPK级联反应的重要调节因子，促进激酶激活并为其信号输出提供关键的时空控制。使用蛋白质组学方法比较两种哺乳动物KSR支架的结合伙伴，我们发现KSR1和KSR2都与ERK级联的激酶组分相互作用，并且在促进rtk介导的ERK信号传导方面具有共同的功能。引人注目的是，我们发现蛋白磷酸酶钙调磷酸酶选择性地与KSR2相互作用，KSR2独特地参与Ca2+介导的ERK信号传导。钙调磷酸酶在响应Ca2+信号的特定位点上使KSR2去磷酸化，从而调节KSR2的定位和活性。此外，我们发现内源性KSR2的缺失会损害INS1胰腺β-细胞和NG108神经母细胞瘤细胞中Ca2+介导的ERK激活和ERK依赖的信号反应。这些发现确定了KSR2是Ca2+调控的ERK支架，并揭示了Ca2+影响Ras到ERK通路信号传导的新机制。
Protein scaffolds have emerged as important regulators of MAPK cascades, facilitating kinase activation and providing crucial spatio/temporal control to their signaling outputs. Using a proteomics approach to compare the binding partners of the two mammalian KSR scaffolds, we find that both KSR1 and KSR2 interact with the kinase components of the ERK cascade and have a common function in promoting RTK-mediated ERK signaling. Strikingly, we find that the protein phosphatase calcineurin selectively interacts with KSR2 and that KSR2 uniquely contributes to Ca2+-mediated ERK signaling. Calcineurin dephosphorylates KSR2 on specific sites in response to Ca2+ signals, thus regulating KSR2 localization and activity. Moreover, we find that depletion of endogenous KSR2 impairs Ca2+-mediated ERK activation and ERK-dependent signaling responses in INS1 pancreatic β-cells and NG108 neuroblastoma cells. These findings identify KSR2 as a Ca2+-regulated ERK scaffold and reveal a new mechanism whereby Ca2+ impacts Ras to ERK pathway signaling.
登录
查看更多内容
影响因子：
9.2
作者：
Ohmachi, M;Rocheleau, CE;Sundaram, MV
通讯作者：
Sundaram, MV
影响因子：
16
作者：
Hao, Nan;Nayak, Sujata;Dohlman, Henrik G.
通讯作者：
Dohlman, Henrik G.
影响因子：
64.8
作者：
Matheny, SA;Chen, CY;White, MA
通讯作者：
White, MA
影响因子：
7.5
作者：
Marshall, CJ
通讯作者：
Marshall, CJ
影响因子：
9.2
作者：
Denouel-Galy, A;Douville, EM;Eychène, A
通讯作者：
Eychène, A