Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
Mol Cell Biol. 2014 Sep 15;34(18):3461-72. doi: 10.1128/MCB.01633-13. Epub 2014 Jul 7.
The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates the activation of the Raf/MEK/extracellular signal-regulated kinase (ERK) signal transduction pathway. KSR1 disruption in mouse embryo fibroblasts (MEFs) abrogates growth factor-induced ERK activation, H-Ras(V12)-induced replicative senescence, and H-Ras(V12)-induced transformation. Caveolin-1 has been primarily described as a major component of the coating structure of caveolae, which can serve as a lipid binding adaptor protein and coordinates the assembly of Ras, Raf, MEK, and ERK. In this study, we show that KSR1 interacts with caveolin-1 and is responsible for MEK and ERK redistribution to caveolin-1-rich fractions. The interaction between KSR1 and caveolin-1 is essential for optimal activation of ERK as a KSR1 mutant unable to interact with caveolin-1 does not efficiently mediate growth factor-induced ERK activation at the early stages of pathway activation. Furthermore, abolishing the KSR1-caveolin-1 interaction increases growth factor demands to promote H-Ras(V12)-induced proliferation and has adverse effects on H-Ras(V12)-induced cellular senescence and transformation. These data show that caveolin-1 is necessary for optimal KSR1-dependent ERK activation by growth factors and oncogenic Ras.
分子支架激酶 Ras 抑制因子 1（KSR1）调节 Raf/MEK/细胞外信号调节激酶（ERK）信号转导途径的激活。在小鼠胚胎成纤维细胞（MEFs）中敲除 KSR1 会破坏生长因子诱导的 ERK 激活、H-Ras(V12)诱导的复制性衰老和 H-Ras(V12)诱导的转化。窖蛋白-1 主要被描述为质膜凹陷（caveolae）的覆盖结构的主要组成部分，可作为脂质结合衔接蛋白，协调 Ras、Raf、MEK 和 ERK 的组装。在这项研究中，我们表明 KSR1 与窖蛋白-1 相互作用，并负责将 MEK 和 ERK 重分配到富含窖蛋白-1 的部分。KSR1 与窖蛋白-1 的相互作用对于 ERK 的最佳激活至关重要，因为无法与窖蛋白-1 相互作用的 KSR1 突变体不能在通路激活的早期阶段有效地介导生长因子诱导的 ERK 激活。此外，消除 KSR1-窖蛋白-1 相互作用会增加生长因子的需求，以促进 H-Ras(V12)诱导的增殖，并对 H-Ras(V12)诱导的细胞衰老和转化产生不利影响。这些数据表明，窖蛋白-1 是生长因子和致癌 Ras 依赖 KSR1 的最佳 ERK 激活所必需的。
