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DOI | 10.1002/2016WR019405 |
TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling | |
Wang, Bin1,2; Jie, Zuliang3; Joo, Donghyun3; Ordureau, Alban4; Liu, Pengda2; Gan, Wenjian2; Guo, Jianping2; Zhang, Jinfang2; North, Brian J.2; Dai, Xiangpeng2; Cheng, Xuhong3; Bian, Xiuwu5,6,7; Zhang, Lingqiang8; Harper, J. Wade4; Sun, Shao-Cong3; Wei, Wenyi2 | |
2017-05-18 | |
发表期刊 | NATURE
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ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2017 |
卷号 | 545期号:7654页码:365-+ |
文章类型 | Article |
语种 | 英语 |
国家 | Peoples R China; USA |
英文摘要 | 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(1). 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(1). Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells. mTORC1 is activated by both nutrients(3-6) and growth factors(7), whereas mTORC2 responds primarily to extracellular cues such as growth-factor-triggered activation of PI3K signalling(8-10). Although both mTOR and G beta L (also known as MLST8) assemble into mTORC1 and mTORC2 (refs 11-15), 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 G beta L dictates the homeostasis of mTORC2 formation and activation. Mechanistically, the TRAF2 E3 ubiquitin ligase promotes K63-linked polyubiquitination of G beta L, which disrupts its interaction with the unique mTORC2 component SIN1 (refs 12-14) to favour mTORC1 formation. By contrast, the OTUD7B deubiquitinase removes polyubiquitin chains from G beta L to promote G beta L interaction with SIN1, facilitating mTORC2 formation in response to various growth signals. Moreover, loss of critical ubiquitination residues in G beta L, by either K305R/K313R mutations or a melanoma-associated G beta L(Delta W297) 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 G beta L-ubiquitination-dependent switch that fine-tunes the dynamic organization and activation of the mTORC2 kinase under both physiological and pathological conditions. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000401466500066 |
WOS关键词 | RAG GTPASES ; PROTEIN-PHOSPHORYLATION ; COMPLEX INTEGRITY ; GAP ACTIVITY ; CANCER ; RAPTOR ; AKT ; ACTIVATION ; GROWTH ; RICTOR |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/21877 |
专题 | 资源环境科学 |
作者单位 | 1.Third Mil Med Univ, Daping Hosp, Inst Surg Res, Dept Gastroenterol, Chongqing 400042, Peoples R China; 2.Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA; 3.Univ Texas MD Anderson Canc Ctr, Dept Immunol, 7455 Fannin St,Box 902, Houston, TX 77030 USA; 4.Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA; 5.Third Mil Med Univ, Southwest Hosp, Minist Educ China, Inst Pathol, Chongqing 400038, Peoples R China; 6.Third Mil Med Univ, Southwest Hosp, Minist Educ China, Southwest Canc Ctr, Chongqing 400038, Peoples R China; 7.Third Mil Med Univ, Southwest Hosp, Minist Educ China, Key Lab Tumor Immunopathol, Chongqing 400038, Peoples R China; 8.Beijing Inst Radiat Med, Collaborat Innovat Ctr Canc Med, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing 100850, Peoples R China |
推荐引用方式 GB/T 7714 | Wang, Bin,Jie, Zuliang,Joo, Donghyun,et al. TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling[J]. NATURE,2017,545(7654):365-+. |
APA | Wang, Bin.,Jie, Zuliang.,Joo, Donghyun.,Ordureau, Alban.,Liu, Pengda.,...&Wei, Wenyi.(2017).TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling.NATURE,545(7654),365-+. |
MLA | Wang, Bin,et al."TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling".NATURE 545.7654(2017):365-+. |
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