PMID- 28489822 OWN - NLM STAT- MEDLINE DCOM- 20170908 LR - 20220812 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 545 IP - 7654 DP - 2017 May 18 TI - TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling. PG - 365-369 LID - 10.1038/nature22344 [doi] AB - The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways. mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer. Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells. mTORC1 is activated by both nutrients and growth factors, whereas mTORC2 responds primarily to extracellular cues such as growth-factor-triggered activation of PI3K signalling. Although both mTOR and GbetaL (also known as MLST8) assemble into mTORC1 and mTORC2 (refs 11, 12, 13, 14, 15), it remains largely unclear what drives the dynamic assembly of these two functionally distinct complexes. Here we show, in humans and mice, that the K63-linked polyubiquitination status of GbetaL dictates the homeostasis of mTORC2 formation and activation. Mechanistically, the TRAF2 E3 ubiquitin ligase promotes K63-linked polyubiquitination of GbetaL, which disrupts its interaction with the unique mTORC2 component SIN1 (refs 12, 13, 14) to favour mTORC1 formation. By contrast, the OTUD7B deubiquitinase removes polyubiquitin chains from GbetaL to promote GbetaL interaction with SIN1, facilitating mTORC2 formation in response to various growth signals. Moreover, loss of critical ubiquitination residues in GbetaL, by either K305R/K313R mutations or a melanoma-associated GbetaL(DeltaW297) truncation, leads to elevated mTORC2 formation, which facilitates tumorigenesis, in part by activating AKT oncogenic signalling. In support of a physiologically pivotal role for OTUD7B in the activation of mTORC2/AKT signalling, genetic deletion of Otud7b in mice suppresses Akt activation and Kras-driven lung tumorigenesis in vivo. Collectively, our study reveals a GbetaL-ubiquitination-dependent switch that fine-tunes the dynamic organization and activation of the mTORC2 kinase under both physiological and pathological conditions. FAU - Wang, Bin AU - Wang B AD - Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China. AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. FAU - Jie, Zuliang AU - Jie Z AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA. FAU - Joo, Donghyun AU - Joo D AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA. FAU - Ordureau, Alban AU - Ordureau A AD - Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Liu, Pengda AU - Liu P AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. FAU - Gan, Wenjian AU - Gan W AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. FAU - Guo, Jianping AU - Guo J AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. FAU - Zhang, Jinfang AU - Zhang J AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. FAU - North, Brian J AU - North BJ AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. FAU - Dai, Xiangpeng AU - Dai X AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. FAU - Cheng, Xuhong AU - Cheng X AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA. FAU - Bian, Xiuwu AU - Bian X AD - Institute of Pathology and Southwest Cancer Center and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. FAU - Zhang, Lingqiang AU - Zhang L AD - State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China. FAU - Harper, J Wade AU - Harper JW AD - Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Sun, Shao-Cong AU - Sun SC AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA. FAU - Wei, Wenyi AU - Wei W AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. LA - eng GR - R01 CA200651/CA/NCI NIH HHS/United States GR - R00 CA181342/CA/NCI NIH HHS/United States GR - R01 GM084459/GM/NIGMS NIH HHS/United States GR - R01 GM094777/GM/NIGMS NIH HHS/United States GR - AG011085/NH/NIH HHS/United States GR - R01 GM095567/GM/NIGMS NIH HHS/United States GR - K99 CA207867/CA/NCI NIH HHS/United States GR - R01 CA177910/CA/NCI NIH HHS/United States GR - R01 GM089763/GM/NIGMS NIH HHS/United States GR - R37 AI064639/AI/NIAID NIH HHS/United States GR - GM095567/NH/NIH HHS/United States GR - R01 AG011085/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20170510 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (MAPKAP1 protein, human) RN - 0 (MLST8 protein, human) RN - 0 (Multiprotein Complexes) RN - 0 (Protein Subunits) RN - 0 (TNF Receptor-Associated Factor 2) RN - 0 (Ubiquitin) RN - 0 (mTOR Associated Protein, LST8 Homolog) RN - 120904-94-1 (Polyubiquitin) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.- (Endopeptidases) RN - EC 3.4.- (OTUD7B protein, human) RN - EC 3.4.19.12 (Otud7b protein, mouse) SB - IM MH - Adaptor Proteins, Signal Transducing/chemistry/metabolism MH - Animals MH - *Carcinogenesis MH - Cell Line MH - Endopeptidases/deficiency/genetics/*metabolism MH - Enzyme Activation MH - Female MH - Homeostasis MH - Humans MH - Lung Neoplasms/enzymology/metabolism/pathology MH - Mechanistic Target of Rapamycin Complex 1 MH - Mechanistic Target of Rapamycin Complex 2 MH - Mice MH - Multiprotein Complexes/biosynthesis/chemistry/*metabolism MH - Phosphorylation MH - Polyubiquitin/metabolism MH - Protein Binding MH - Protein Subunits/chemistry/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - *Signal Transduction MH - TNF Receptor-Associated Factor 2/*metabolism MH - TOR Serine-Threonine Kinases/biosynthesis/chemistry/*metabolism MH - Ubiquitin/*metabolism MH - *Ubiquitination MH - mTOR Associated Protein, LST8 Homolog PMC - PMC5695540 MID - NIHMS920035 COIS- The authors declare no competing financial interests. Readers are welcome to comment on the online version of the paper. EDAT- 2017/05/11 06:00 MHDA- 2017/09/09 06:00 PMCR- 2017/11/20 CRDT- 2017/05/11 06:00 PHST- 2016/02/07 00:00 [received] PHST- 2017/04/04 00:00 [accepted] PHST- 2017/05/11 06:00 [pubmed] PHST- 2017/09/09 06:00 [medline] PHST- 2017/05/11 06:00 [entrez] PHST- 2017/11/20 00:00 [pmc-release] AID - nature22344 [pii] AID - 10.1038/nature22344 [doi] PST - ppublish SO - Nature. 2017 May 18;545(7654):365-369. doi: 10.1038/nature22344. Epub 2017 May 10.