PMID- 26584640 OWN - NLM STAT- MEDLINE DCOM- 20161012 LR - 20220321 IS - 1748-7838 (Electronic) IS - 1001-0602 (Print) IS - 1001-0602 (Linking) VI - 26 IP - 1 DP - 2016 Jan TI - mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR. PG - 46-65 LID - 10.1038/cr.2015.133 [doi] AB - 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. FAU - Yin, Yancun AU - Yin Y AD - State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. FAU - Hua, Hui AU - Hua H AD - Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. FAU - Li, Minjing AU - Li M AD - Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong 264003, China. FAU - Liu, Shu AU - Liu S AD - State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. FAU - Kong, Qingbin AU - Kong Q AD - State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. FAU - Shao, Ting AU - Shao T AD - State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. FAU - Wang, Jiao AU - Wang J AD - School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China. FAU - Luo, Yuanming AU - Luo Y AD - State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. FAU - Wang, Qian AU - Wang Q AD - State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. FAU - Luo, Ting AU - Luo T AD - Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. FAU - Jiang, Yangfu AU - Jiang Y AD - State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151120 PL - England TA - Cell Res JT - Cell research JID - 9425763 RN - 0 (Carrier Proteins) RN - 0 (Multiprotein Complexes) RN - 0 (RICTOR protein, human) RN - 0 (Rapamycin-Insensitive Companion of mTOR Protein) RN - 42HK56048U (Tyrosine) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.10.1 (Receptor, Insulin) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Carrier Proteins/metabolism MH - Cell Line, Tumor MH - Cell Proliferation MH - HEK293 Cells MH - Hep G2 Cells MH - Humans MH - Mechanistic Target of Rapamycin Complex 2 MH - Multiprotein Complexes/*metabolism MH - Phosphorylation MH - Protein-Tyrosine Kinases/*metabolism MH - Rapamycin-Insensitive Companion of mTOR Protein MH - Receptor, IGF Type 1/*metabolism MH - Receptor, Insulin/*metabolism MH - Sirolimus/metabolism MH - TOR Serine-Threonine Kinases/*metabolism MH - Tyrosine/*metabolism PMC - PMC4816127 EDAT- 2015/11/21 06:00 MHDA- 2016/10/13 06:00 PMCR- 2017/01/01 CRDT- 2015/11/21 06:00 PHST- 2015/05/06 00:00 [received] PHST- 2015/09/15 00:00 [revised] PHST- 2015/10/08 00:00 [accepted] PHST- 2015/11/21 06:00 [entrez] PHST- 2015/11/21 06:00 [pubmed] PHST- 2016/10/13 06:00 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - cr2015133 [pii] AID - 10.1038/cr.2015.133 [doi] PST - ppublish SO - Cell Res. 2016 Jan;26(1):46-65. doi: 10.1038/cr.2015.133. Epub 2015 Nov 20.