title: mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR.
abstract: 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.
authors.affiliation: State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yancun
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Hua
authors.affiliation: Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong 264003, China.
authors.forename: Minjing
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Shao
authors.affiliation: School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Biotherapy, Section of Oncogene, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yangfu
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014443:Tyrosine; C546842:MTOR protein, human; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus