Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt.
Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt.
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DOI：
10.1016/j.molcel.2016.04.023
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发表时间：
2016-06-16
期刊：
影响因子：
16
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Zhang J;Xu K;Liu P;Geng Y;Wang B;Gan W;Guo J;Wu F;Chin YR;Berrios C;Lien EC;Toker A;DeCaprio JA;Sicinski P;Wei W
视网膜母细胞瘤（Rb）蛋白主要通过抑制调控细胞周期进程的转录因子E2 F家族来发挥其肿瘤抑制功能。然而，它仍然在很大程度上难以捉摸是否过度磷酸化，非E2 F1相互作用的形式，Rb有任何生理作用。在这里，我们报告说，过度磷酸化Rb直接结合，并抑制mTORC 2的功能，但不是mTORC 1。从机制上讲，Rb（而不是p107或p130）与Sin 1相互作用，并阻断Akt进入mTORC 2，导致Akt活化减弱，对化疗药物的敏感性增加。因此，通过耗尽细胞周期蛋白D或使用CDK 4/6抑制剂抑制Rb磷酸化释放Rb介导的mTORC 2抑制。这反过来又导致Akt活化升高，从而在Rb-精通细胞中赋予对化疗药物的抗性，这可以用Akt抑制剂减弱。因此，我们的工作为CDK 4/6和Akt抑制剂在治疗Rb-活性癌症中的协同使用提供了分子基础。Zhang等报道，过度磷酸化的Rb也部分通过结合Sin 1抑制mTORC 2介导的Akt活化而发挥肿瘤抑制作用。因此，通过消耗细胞周期蛋白D或CDK 4/6抑制剂来抑制Rb磷酸化导致Akt-pS473升高，从而赋予耐药性，其可以被Akt抑制剂减弱。
The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell cycle progression. However, it remains largely elusive whether hyper-phosphorylated, non-E2F1-interacting form, of Rb has any physiological role. Here, we report that hyper-phosphorylated Rb directly binds to, and suppresses the function of mTORC2, but not mTORC1. Mechanistically, Rb, but not p107 nor p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D, or using CDK4/6 inhibitors, releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer. Zhang et al report that hyper-phosphorylated Rb also plays a tumor suppressive role partly through binding Sin1 to inhibit mTORC2-mediated activation of Akt. Thus, inhibiting Rb phosphorylation by depletion of cyclin D or CDK4/6 inhibitor leads to elevated Akt-pS473 to confer drug resistance, which can be attenuated by Akt inhibitors.