Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability

doi:10.1016/j.celrep.2017.06.063

科研成果详情

题名	Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability
作者	Huang, Zhifeng1; Tan, Yi1,2; Gu, Junlian 2,3; Liu, Yang 4; Song, Lintao1; Niu, Jianlou1,4; Zhao, Longwei1; Srinivasan, Lakshmi 4; Lin, Qian1,2; Deng, Jingjing 5; Li, Yang 6; Conklin, Daniel J.3; Neubert, Thomas A.5; Cai, Lu 2; Li, Xiaokun1; Mohammadi, Moosa 4
发表日期	2017-08-15
发表期刊	CELL REPORTS 影响因子和分区
语种	英语
原始文献类型	Article
关键词	FGF receptor db/db mice fibroblast growth factor 1 glucose uptake heparin sulfate metabolism mitogenesis receptor dimerization signaling pathways threshold.
其他关键词	FIBROBLAST-GROWTH-FACTOR ; STRUCTURAL BASIS ; BETA-KLOTHO ; FACTOR FAMILY ; ACTIVATION ; SPECIFICITY ; PROLIFERATION ; MECHANISMS ; HEPARIN ; BIOLOGY
摘要	The recent discovery of metabolic roles for fibroblast growth factor 1 (FGF1) in glucose homeostasis has expanded the functions of this classically known mitogen. To dissect the molecular basis for this functional pleiotropy, we engineered an FGF1 partial agonist carrying triple mutations (FGF1 DHBS) that diminished its ability to induce heparan sulfate (HS)-assisted FGF receptor (FGFR) dimerization and activation. FGF1 DHBS exhibited a severely reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1 in vitro and in vivo. Hence, suboptimal FGFR activation by a weak FGF1-FGFR dimer is sufficient to evoke a metabolic response, whereas full FGFR activation by stable and sustained dimerization is required to elicit a mitogenic response. In addition to providing a physical basis for the diverse activities of FGF1, our findings will impact ongoing drug discoveries targeting FGF1 and related FGFs for the treatment of a variety of human diseases.
资助项目	NIH NIDCRUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [DE13686]; NINDSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [P30 NS050276, S10 RR027990]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81102486, 81273509]; Natural Science Foundation of Zhejiang Province, ChinaNatural Science Foundation of Zhejiang Province [LQ15H310005]; Key Project from Science Technology Department of Zhejiang Province, China [2017C03030]; Project from Science Technology Department of Wenzhou, China [Y20140734]; American Diabetes AssociationAmerican Diabetes Association; Juvenile Diabetes Research FoundationJuvenile Diabetes Research Foundation [1-13-JF-53, 1-15-BS-018, 1-INO-2014-122-A-N]; NATIONAL CENTER FOR RESEARCH RESOURCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [S10RR027990] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [R01DE013686] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [P20GM103492] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [P30NS050276] Funding Source: NIH RePORTER
出版者	CELL PRESS
出版地	CAMBRIDGE
ISSN	2211-1247
卷号	20 期号:7 页码:1717-1728
DOI	10.1016/j.celrep.2017.06.063
页数	12
WOS类目	Cell Biology
WOS研究方向	Cell Biology
WOS记录号	WOS:000407924300019
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	28813681
PMC记录号	PMC5821125
SCOPUSEID	2-s2.0-85027890892
自科自定义期刊分类	T3(B)类
通讯作者地址	[Li, Xiaokun]School of Pharmacy & Center for Structural Biology,Wenzhou Medical University,Wenzhou,325035,China
Scopus学科分类	Biochemistry, Genetics and Molecular Biology (all)
TOP期刊	TOP期刊
引用统计	被引频次：48[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/10131
专题	药学院（分析测试中心）
通讯作者	Li, Xiaokun
作者单位	1.School of Pharmacy & Center for Structural Biology,Wenzhou Medical University,Wenzhou,325035,China; 2.Pediatric Research Institute,University of Louisville School of Medicine,Louisville,40202,United States; 3.Diabetes and Obesity Center,University of Louisville School of Medicine,Louisville,40202,United States; 4.Department of Biochemistry & Molecular Pharmacology,New York University School of Medicine,New York,10016,United States; 5.Department of Cell Biology and Skirball Institute of Biomolecular Medicine,New York University School of Medicine,New York,10016,United States; 6.Amgen Inc.,1120 Veterans Boulevard,South San Francisco,94080,United States
第一作者单位	药学院（分析测试中心）
通讯作者单位	药学院（分析测试中心）
第一作者的第一单位	药学院（分析测试中心）
推荐引用方式 GB/T 7714	Huang, Zhifeng,Tan, Yi,Gu, Junlian,et al. Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability[J]. CELL REPORTS,2017,20(7):1717-1728.
APA	Huang, Zhifeng., Tan, Yi., Gu, Junlian., Liu, Yang., Song, Lintao., ... & Mohammadi, Moosa. (2017). Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability. CELL REPORTS, 20(7), 1717-1728.
MLA	Huang, Zhifeng,et al."Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability".CELL REPORTS 20.7(2017):1717-1728.