气候变化领域集成服务门户(CCPortal): RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity

CCPortal

DOI	10.1073/pnas.2103261118
	RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity
	Castel P.; Dharmaiah S.; Sale M.J.; Messing S.; Rizzuto G.; Cuevas-Navarro A.; Cheng A.; Trnka M.J.; Urisman A.; Esposito D.; Simanshu D.K.; McCormick F.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:33
英文摘要	RAS proteins are molecular switches that interact with effector proteins when bound to guanosine triphosphate, stimulating downstream signaling in response to multiple stimuli. Although several canonical downstream effectors have been extensively studied and tested as potential targets for RAS-driven cancers, many of these remain poorly characterized. In this study, we undertook a biochemical and structural approach to further study the role of Sin1 as a RAS effector. Sin1 interacted predominantly with KRAS isoform 4A in cells through an atypical RAS-binding domain that we have characterized by X-ray crystallography. Despite the essential role of Sin1 in the assembly and activity of mTORC2, we find that the interaction with RAS is not required for these functions. Cells and mice expressing a mutant of Sin1 that is unable to bind RAS are proficient for activation and assembly of mTORC2. Our results suggest that Sin1 is a bona fide RAS effector that regulates downstream signaling in an mTORC2-independent manner. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	KRAS; MTORC2; RAS; RBD; Sin1
语种	英语
scopus关键词	cell protein; K ras protein; mammalian target of rapamycin complex 2; Ras protein; Sin1 protein; unclassified drug; isoprotein; KRAS protein, human; mammalian target of rapamycin complex 2; MAPKAP1 protein, human; protein p21; signal transducing adaptor protein; adult; animal experiment; animal tissue; Article; controlled study; enzyme activity; human; human cell; mouse; nonhuman; protein analysis; protein assembly; protein binding; protein domain; protein function; protein protein interaction; protein structure; signal transduction; X ray crystallography; gene expression regulation; genetics; HEK293 cell line; mass spectrometry; metabolism; molecular model; physiology; protein conformation; Adaptor Proteins, Signal Transducing; Gene Expression Regulation; HEK293 Cells; Humans; Mass Spectrometry; Mechanistic Target of Rapamycin Complex 2; Models, Molecular; Protein Conformation; Protein Isoforms; Proto-Oncogene Proteins p21(ras); Signal Transduction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251054
作者单位	Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, United States; National Cancer Institute (NCI) RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, United States; Department of Anatomic Pathology, University of California, San Francisco, CA 94158, United States; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, United States; Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, United States
推荐引用方式 GB/T 7714	Castel P.,Dharmaiah S.,Sale M.J.,et al. RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity[J],2021,118(33).
APA	Castel P..,Dharmaiah S..,Sale M.J..,Messing S..,Rizzuto G..,...&McCormick F..(2021).RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity.Proceedings of the National Academy of Sciences of the United States of America,118(33).
MLA	Castel P.,et al."RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity".Proceedings of the National Academy of Sciences of the United States of America 118.33(2021).