ERK1/2 Phosphorylate Raptor to Promote Ras-dependent Activation of mTOR Complex 1 (mTORC1)
ERK1/2 Phosphorylate Raptor to Promote Ras-dependent Activation of mTOR Complex 1 (mTORC1)
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DOI：
10.1074/jbc.m110.159046
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发表时间：
2011-01-07
影响因子：
4.8
通讯作者：
Roux, Philippe P.
中科院分区：
文献类型：
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作者：
Carriere, Audrey;Romeo, Yves;Roux, Philippe P.
Ras/丝裂原活化蛋白激酶（MAPK）途径通过激活特定的转录和翻译程序来调节多种细胞过程。Ras/MAPK信号传导促进mRNA翻译和蛋白质合成，但这种调控的确切分子机制尚不清楚。越来越多的证据表明，哺乳动物雷帕霉素靶点（mTOR）在这一过程中起着至关重要的作用。在这里，我们展示了Raptor， mTOR复合物1 （mTORC1）的基本支架蛋白，在Ras/MAPK途径激活后，在脯氨酸定向位点上被磷酸化。我们发现ERK1和ERK2在细胞内与Raptor相互作用，并介导其在体内和体外的磷酸化。通过质谱分析和磷酸化特异性抗体，我们在Raptor中发现了三个脯氨酸导向的残基，Ser(8), Ser（696）和Ser(863)，它们被ERK1/2直接磷酸化。Raptor磷酸化缺陷等位基因的表达表明，ERK1/2对这些位点的磷酸化通常会促进mTORC1活性和向下游底物（如4E-BP1）发送信号。我们的数据提供了一种新的调控机制，Ras/MAPK通路的有丝分裂和致癌激活促进mTOR信号传导。
The Ras/mitogen-activated protein kinase (MAPK) pathway regulates a variety of cellular processes by activating specific transcriptional and translational programs. Ras/MAPK signaling promotes mRNA translation and protein synthesis, but the exact molecular mechanisms underlying this regulation remain poorly understood. Increasing evidence suggests that the mammalian target of rapamycin (mTOR) plays an essential role in this process. Here, we show that Raptor, an essential scaffolding protein of the mTOR complex 1 (mTORC1), becomes phosphorylated on proline-directed sites following activation of the Ras/MAPK pathway. We found that ERK1 and ERK2 interact with Raptor in cells and mediate its phosphorylation in vivo and in vitro. Using mass spectrometry and phosphospecific antibodies, we found three proline-directed residues within Raptor, Ser(8), Ser(696), and Ser(863), which are directly phosphorylated by ERK1/2. Expression of phosphorylation-deficient alleles of Raptor revealed that phosphorylation of these sites by ERK1/2 normally promotes mTORC1 activity and signaling to downstream substrates, such as 4E-BP1. Our data provide a novel regulatory mechanism by which mitogenic and oncogenic activation of the Ras/MAPK pathway promotes mTOR signaling.