Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1.
Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1.
复制标题
丙酮酸激酶 M2 通过磷酸化 AKT1S1 激活 mTORC1。
DOI：
10.1038/srep21524
复制
发表时间：
2016-02-15
影响因子：
4.6
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
He CL;Bian YY;Xue Y;Liu ZX;Zhou KQ;Yao CF;Lin Y;Zou HF;Luo FX;Qu YY;Zhao JY;Ye ML;Zhao SM;Xu W
在癌细胞中，需要激素和营养信号才能激活的雷帕霉素复合体1(MTORC1)的哺乳动物靶点被结构性激活。我们发现，过表达的丙酮酸激酶M2(PKM2)通过磷酸化mTORC1抑制物AKT1底物1(AKT1S1)来激活mTORC1信号。在肾细胞癌(RCC)的蛋白质组中，一项无偏倚的定量磷酸蛋白质组学研究确定了974个PKM2底物，包括AKT1S1的丝氨酸202和丝氨酸203(S202/203)。PKM2将AKT1S1的S202/203磷酸化后释放出猛禽的AKT1S1，并促进其与14-3-3的结合，导致mTORC1信号的激素和营养信号非依赖性激活，加速癌细胞的致癌生长和自噬抑制。Tepp-46抑制S202/203的磷酸化逆转了这些作用。在肾癌和乳腺癌中，PKM2的过度表达与S202/203磷酸化升高、激活mTORC1和抑制自噬相关。我们的结果提供了第一个PKM2的磷酸组，并揭示了癌细胞中mTORC1的结构性激活机制。
In cancer cells, the mammalian target of rapamycin complex 1 (mTORC1) that requires hormonal and nutrient signals for its activation, is constitutively activated. We found that overexpression of pyruvate kinase M2 (PKM2) activates mTORC1 signaling through phosphorylating mTORC1 inhibitor AKT1 substrate 1 (AKT1S1). An unbiased quantitative phosphoproteomic survey identified 974 PKM2 substrates, including serine202 and serine203 (S202/203) of AKT1S1, in the proteome of renal cell carcinoma (RCC). Phosphorylation of S202/203 of AKT1S1 by PKM2 released AKT1S1 from raptor and facilitated its binding to 14-3-3, resulted in hormonal- and nutrient-signals independent activation of mTORC1 signaling and led accelerated oncogenic growth and autophagy inhibition in cancer cells. Decreasing S202/203 phosphorylation by TEPP-46 treatment reversed these effects. In RCCs and breast cancers, PKM2 overexpression was correlated with elevated S202/203 phosphorylation, activated mTORC1 and inhibited autophagy. Our results provided the first phosphorylome of PKM2 and revealed a constitutive mTORC1 activating mechanism in cancer cells.