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Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability.
Cell Rep 2017; 20(7):1717-1728CR

Abstract

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 (FGF1ΔHBS) that diminished its ability to induce heparan sulfate (HS)-assisted FGF receptor (FGFR) dimerization and activation. FGF1ΔHBS 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.

Authors+Show Affiliations

School of Pharmacy & Center for Structural Biology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.School of Pharmacy & Center for Structural Biology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Pediatric Research Institute, University of Louisville School of Medicine, Louisville, KY 40202, USA.Pediatric Research Institute, University of Louisville School of Medicine, Louisville, KY 40202, USA; Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.School of Pharmacy & Center for Structural Biology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.School of Pharmacy & Center for Structural Biology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.School of Pharmacy & Center for Structural Biology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.School of Pharmacy & Center for Structural Biology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Pediatric Research Institute, University of Louisville School of Medicine, Louisville, KY 40202, USA.Department of Cell Biology and Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.Department of Cell Biology and Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.Pediatric Research Institute, University of Louisville School of Medicine, Louisville, KY 40202, USA.School of Pharmacy & Center for Structural Biology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: xiaokunli@wzmu.edu.cn.Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: moosa.mohammadi@nyumc.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28813681

Citation

Huang, Zhifeng, et al. "Uncoupling the Mitogenic and Metabolic Functions of FGF1 By Tuning FGF1-FGF Receptor Dimer Stability." Cell Reports, vol. 20, no. 7, 2017, pp. 1717-1728.
Huang Z, Tan Y, Gu J, et al. Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability. Cell Rep. 2017;20(7):1717-1728.
Huang, Z., Tan, Y., Gu, J., Liu, Y., Song, L., Niu, J., ... Mohammadi, M. (2017). Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability. Cell Reports, 20(7), pp. 1717-1728. doi:10.1016/j.celrep.2017.06.063.
Huang Z, et al. Uncoupling the Mitogenic and Metabolic Functions of FGF1 By Tuning FGF1-FGF Receptor Dimer Stability. Cell Rep. 2017 08 15;20(7):1717-1728. PubMed PMID: 28813681.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability. AU - Huang,Zhifeng, AU - Tan,Yi, AU - Gu,Junlian, AU - Liu,Yang, AU - Song,Lintao, AU - Niu,Jianlou, AU - Zhao,Longwei, AU - Srinivasan,Lakshmi, AU - Lin,Qian, AU - Deng,Jingjing, AU - Li,Yang, AU - Conklin,Daniel J, AU - Neubert,Thomas A, AU - Cai,Lu, AU - Li,Xiaokun, AU - Mohammadi,Moosa, PY - 2017/02/11/received PY - 2017/05/11/revised PY - 2017/06/20/accepted PY - 2017/8/17/entrez PY - 2017/8/17/pubmed PY - 2018/4/25/medline KW - FGF receptor KW - db/db mice KW - fibroblast growth factor 1 KW - glucose uptake KW - heparin sulfate KW - metabolism KW - mitogenesis KW - receptor dimerization KW - signaling pathways KW - threshold SP - 1717 EP - 1728 JF - Cell reports JO - Cell Rep VL - 20 IS - 7 N2 - 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 (FGF1ΔHBS) that diminished its ability to induce heparan sulfate (HS)-assisted FGF receptor (FGFR) dimerization and activation. FGF1ΔHBS 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. SN - 2211-1247 UR - https://www.unboundmedicine.com/medline/citation/28813681/Uncoupling_the_Mitogenic_and_Metabolic_Functions_of_FGF1_by_Tuning_FGF1_FGF_Receptor_Dimer_Stability_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-1247(17)30894-X DB - PRIME DP - Unbound Medicine ER -