State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
J Biol Chem. 2011 Sep 9;286(36):31501-11. doi: 10.1074/jbc.M111.233122. Epub 2011 Jul 14.
Cell growth is influenced by environmental stress. Mammalian target of rapamycin (mTOR), the central regulator of cell growth, can be positively or negatively regulated by various stresses through different mechanisms. The p38 MAP kinase pathway is essential in cellular stress responses. Activation of MK2, a downstream kinase of p38α, enhances mTOR complex 1 (mTORC1) activity by preventing TSC2 from inhibiting mTOR activation. The p38β-PRAK cascade targets Rheb to inhibit mTORC1 activity upon glucose depletion. Here we show the activation of p38β participates in activation of mTOR complex 1 (mTORC1) induced by arsenite but not insulin, nutrients, anisomycin, or H(2)O(2). Arsenite treatment of cells activates p38β and induces interaction between p38β and Raptor, a regulatory component of mTORC1, resulting in phosphorylation of Raptor on Ser(863) and Ser(771). The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation. Our results shown here and in previous work demonstrate that the p38 pathway can regulate different components of the mTORC1 pathway, and that p38β can target different substrates to either positively or negatively regulate mTORC1 activation when a cell encounters different environmental stresses.
细胞生长受环境压力影响。哺乳动物雷帕霉素靶蛋白（mTOR）是细胞生长的核心调节剂，可通过不同机制受各种应激正向或负向调节。p38MAP 激酶途径是细胞应激反应所必需的。p38α 的下游激酶 MK2 的激活通过阻止 TSC2 抑制 mTOR 激活来增强 mTOR 复合物 1（mTORC1）的活性。p38β-PRAK 级联反应在葡萄糖耗竭时靶向 Rheb 以抑制 mTORC1 活性。在这里，我们显示 p38β 的激活参与了亚砷酸盐诱导的 mTOR 复合物 1（mTORC1）的激活，但不参与胰岛素、营养物质、放线菌酮或 H2O2 的激活。细胞中的亚砷酸盐处理激活 p38β 并诱导 p38β 与 Raptor 之间的相互作用，Raptor 是 mTORC1 的调节成分，导致 Raptor 在 Ser（863）和 Ser（771）上磷酸化。这些位点上的 Raptor 磷酸化增强了 mTORC1 的活性，并在很大程度上促进了亚砷酸盐诱导的 mTORC1 激活。我们这里和以前的工作结果表明，p38 途径可以调节 mTORC1 途径的不同成分，并且当细胞遇到不同的环境压力时，p38β 可以针对不同的底物来正向或负向调节 mTORC1 的激活。
