Dissecting the biology of mTORC1 beyond rapamycin.
Dissecting the biology of mTORC1 beyond rapamycin.
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DOI：
10.1126/scisignal.abe0161
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发表时间：
2021-09-21
影响因子：
7.3
通讯作者：
James DE
中科院分区：
文献类型：
--
作者：
Yang G;Francis D;Krycer JR;Larance M;Zhang Z;Novotny CJ;Diaz-Vegas A;Shokat KM;James DE
雷帕霉素延长了许多生物体的最大寿命，并增强了对饥饿的抵抗力。雷帕霉素的有益作用被认为是通过其对雷帕霉素复合物1（mTORC 1）的机制靶点的抑制作用介导的，尽管其仅部分抑制mTORC 1的激酶活性。已经开发了其他mTOR激酶抑制剂，如Torin-1，但这些很容易与mTORC 2交叉反应。在这里，我们报告了第三代mTOR抑制剂RapaLink1的独特特征。我们发现，低剂量的RapaLink1抑制了所有测试的mTORC1底物的磷酸化，包括那些磷酸化对雷帕霉素的抑制敏感或耐药的底物，即使在长时间治疗后也不影响mTORC2活性。与雷帕霉素相比，RapaLink1对mTORC1的抑制效果更好，并有效地阻断细胞增殖和诱导自噬。此外，使用RapaLink1，我们证明了mTORC 1和mTORC 2对细胞糖酵解和葡萄糖摄取产生不同的影响。最后，我们发现RapaLink1和雷帕霉素对果蝇的饥饿抗性有相反的作用。与RapaLink1的作用一致，mTORC1活性的遗传阻断使果蝇对饥饿更敏感，反映了mTORC1网络的复杂性，该网络超出了雷帕霉素可以抑制的作用。这些发现扩展了我们对mTOR生物学的理解，并为雷帕霉素的一些有益作用提供了见解。
Rapamycin extends maximal lifespan and increases resistance to starvation in many organisms. The beneficial effects of rapamycin are thought to be mediated by its inhibitory effects on the mechanistic target of rapamycin complex 1 (mTORC1), although it only partially inhibits the kinase activity of mTORC1. Other mTOR kinase inhibitors have been developed, such as Torin-1, but these readily cross react with mTORC2. Here, we report the distinct characteristics of a third generation mTOR inhibitor called RapaLink1. We found that low doses of RapaLink1 inhibited the phosphorylation of all mTORC1 substrates tested, including those whose phosphorylation is sensitive or resistant to inhibition by rapamycin, without affecting mTORC2 activity even after prolonged treatment. Compared with rapamycin, RapaLink1 showed better efficacy for inhibiting mTORC1 and potently blocked cell proliferation and induced autophagy. Moreover, using RapaLink1, we demonstrated that mTORC1 and mTORC2 exerted differential effects on cell glycolysis and glucose uptake. Finally, we found that RapaLink1 and rapamycin had opposing effects on starvation resistance in Drosophila. Consistent with the effects of RapaLink1, genetic blockade of mTORC1 activity made flies more sensitive to starvation, reflecting the complexity of the mTORC1 network that extends beyond effects that can be inhibited by rapamycin. These findings extend our understanding of mTOR biology and provide insights into some of the beneficial effects of rapamycin.
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影响因子：
8.1
作者：
Kleinert M;Sylow L;Fazakerley DJ;Krycer JR;Thomas KC;Oxbøll AJ;Jordy AB;Jensen TE;Yang G;Schjerling P;Kiens B;James DE;Ruegg MA;Richter EA
通讯作者：
Richter EA
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
3.3
作者：
Jung, Chang Hwa;Jun, Chang Bong;Kim, Do-Hyung
通讯作者：
Kim, Do-Hyung
影响因子：
5.8
作者：
Arganda-Carreras, Ignacio;Kaynig, Verena;Seung, H. Sebastian
通讯作者：
Seung, H. Sebastian