气候变化领域集成服务门户(CCPortal): Recurrent high-impact mutations at cognate structural positions in class A G protein-coupled receptors expressed in tumors

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DOI	10.1073/pnas.2113373118
	Recurrent high-impact mutations at cognate structural positions in class A G protein-coupled receptors expressed in tumors
	Huh E.; Gallion J.; Agosto M.A.; Wright S.J.; Wensel T.G.; Lichtarge O.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:51
英文摘要	G protein-coupled receptors (GPCRs) are the largest family of human proteins. They have a common structure and, signaling through a much smaller set of G proteins, arrestins, and effectors, activate downstream pathways that often modulate hallmark mechanisms of cancer. Because there are many more GPCRs than effectors, mutations in different receptors could perturb signaling similarly so as to favor a tumor. We hypothesized that somatic mutations in tumor samples may not be enriched within a single gene but rather that cognate mutations with similar effects on GPCR function are distributed across many receptors. To test this possibility, we systematically aggregated somatic cancer mutations across class A GPCRs and found a nonrandom distribution of positions with variant amino acid residues. Individual cancer types were enriched for highly impactful, recurrent mutations at selected cognate positions of known functional motifs. We also discovered that no single receptor drives this pattern, but rather multiple receptors contain amino acid substitutions at a few cognate positions. Phenotypic characterization suggests these mutations induce perturbation of G protein activation and/or β-arrestin recruitment. These data suggest that recurrent impactful oncogenic mutations perturb different GPCRs to subvert signaling and promote tumor growth or survival. The possibility that multiple different GPCRs could moonlight as drivers or enablers of a given cancer through mutations located at cognate positions across GPCR paralogs opens a window into cancer mechanisms and potential approaches to therapeutics. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cancer; Evolutionary action (EA); G protein-coupled receptor (GPCR); Mutational signatures; β-arrestin
语种	英语
scopus关键词	beta arrestin; calcium; G protein coupled receptor; computer simulation; enzyme linked immunosorbent assay; gene expression regulation; genetics; human; metabolism; mutation; neoplasm; physiology; protein conformation; tumor cell line; beta-Arrestins; Calcium; Cell Line, Tumor; Computer Simulation; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Humans; Mutation; Neoplasms; Protein Conformation; Receptors, G-Protein-Coupled
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/250916
作者单位	Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, United States; Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, United States; Mercury Data Science, Houston, TX 77098, United States; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, United States; Retina and Optic Nerve Research Laboratory, Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 4R2, Canada; Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
推荐引用方式 GB/T 7714	Huh E.,Gallion J.,Agosto M.A.,et al. Recurrent high-impact mutations at cognate structural positions in class A G protein-coupled receptors expressed in tumors[J],2021,118(51).
APA	Huh E.,Gallion J.,Agosto M.A.,Wright S.J.,Wensel T.G.,&Lichtarge O..(2021).Recurrent high-impact mutations at cognate structural positions in class A G protein-coupled receptors expressed in tumors.Proceedings of the National Academy of Sciences of the United States of America,118(51).
MLA	Huh E.,et al."Recurrent high-impact mutations at cognate structural positions in class A G protein-coupled receptors expressed in tumors".Proceedings of the National Academy of Sciences of the United States of America 118.51(2021).