Volume 26, No 1, Jan 2016

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 26 Issue 1, January 2016: 46-65

ORIGINAL ARTICLES

mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR

Yancun Yin¹, Hui Hua², Minjing Li³, Shu Liu¹, Qingbin Kong¹, Ting Shao¹, Jiao Wang⁴, Yuanming Luo⁵, Qian Wang⁵, Ting Luo⁶ and Yangfu Jiang¹

¹State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
²Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
³Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong 264003, China
⁴School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China
⁵State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
⁶Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China Correspondence: Yangfu Jiang, Tel: 86-28-85164044; Fax: 86-28-85164046(jyangfu@scu.edu.cn)

Mammalian target of rapamycin (mTOR) is a core component of raptor-mTOR (mTORC1) and rictor-mTOR (mTORC2) complexes that control diverse cellular processes. Both mTORC1 and mTORC2 regulate several elements downstream of type I insulin-like growth factor receptor (IGF-IR) and insulin receptor (InsR). However, it is unknown whether and how mTOR regulates IGF-IR and InsR themselves. Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR/InsR. Rapamycin induces the tyrosine phosphorylation and activation of IGF-IR/InsR, which is largely dependent on rictor and mTOR. Moreover, mTORC2 promotes ligand-induced activation of IGF-IR/InsR. IGF- and insulin-induced IGF-IR/InsR phosphorylation is significantly compromised in rictor-null cells. Insulin receptor substrate (IRS) directly interacts with SIN1 thereby recruiting mTORC2 to IGF-IR/InsR and promoting rapamycin- or ligand-induced phosphorylation of IGF-IR/InsR. mTOR exhibits tyrosine kinase activity towards the general tyrosine kinase substrate poly(Glu-Tyr) and IGF-IR/InsR. Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively. These effects are independent of the intrinsic kinase activity of IGF-IR/InsR, as determined by assays on kinase-dead IGF-IR/InsR mutants. While both rictor and mTOR immunoprecitates from rictor+/+ MCF-10A cells exhibit tyrosine kinase activity towards IGF-IR and InsR, mTOR immunoprecipitates from rictor−/− MCF-10A cells do not induce IGF-IR and InsR phosphorylation. Phosphorylation-deficient mutation of residue Tyr1131 in IGF-IR or Tyr1146 in InsR abrogates the activation of IGF-IR/InsR by mTOR. Finally, overexpression of rictor promotes IGF-induced cell proliferation. Our work identifies mTOR as a dual-specificity kinase and clarifies how mTORC2 promotes IGF-IR/InsR activation.

10.1038/cr.2015.133

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