Fibroblast growth factor (FGF) signaling plays pleiotropic roles in mammalian development and metabolism, and disease. The paracrine FGF1, FGF4, FGF7, FGF8, and FGF9 subfamilies play essential roles in spermatogenesis, mesoderm induction, somitogenesis, organogenesis, and pattern formation, whereas the FGF19 subfamily acts in an endocrine fashion to regulate major metabolic processes including glucose, lipid, cholesterol, and bile acid metabolism, and phosphate/vitamin D homeostasis. The diverse activities of FGFs are transmitted by the FGF receptor (FGFR) subfamily of receptor tyrosine kinases (RTKs). Perturbed FGF signaling leads to numerous human diseases, including skeletal, reproductive syndromes, hearing loss, renal phosphate wasting, neurodegenerative disorders, and cancer. Several paracrine FGFs and all the endocrine FGFs are being pursued for drug development. The four specific aims of this competing renewal are: I. Characterize the structural basis by which epithelially-expressed FGF4 and FGF9 subfamilies attain their specificity towards mesenchymally-expressed FGFRc isoforms. II. Elucidate the structural basis by which a/bKlotho co-receptors promote signaling by the endocrine FGFs. III. Dissect the role of A-loop tyrosine phosphorylation in the hyperactivation of FGFR tyrosine kinase by pathogenic gain-of-function mutations. IV. Elucidate the structural basis by which FGFR recruits and phosphorylates FRS2a. Recombinant protein expression and engineering, x-ray crystallography, Surface Plasmon Resonance (SPR) spectroscopy, isothermal titration calorimetry (ITC), steady-state kinetics analysis, and time-resolved mass spectrometry will be used to accomplish the Specific Aims of this proposal. The structural and biophysical/biochemical results obtained will also be validated using cell- and animal-based assays. The data obtained under Aim I should provide molecular insights into the roles of paracrine FGFs in embryonic development and also facilitate the discovery of drugs for tissue repair and bioengineering, promotion of self- renewal and differentiation of human embryonic stem cells for cell-replacement therapy. The data generated under Aim II should enhance our understanding of the role of endocrine FGFs in human metabolism and provide blueprints for drug discovery for major human diseases including diabetes, obesity, hypercholesterolemia, colon cancer, and chronic kidney disease, most of which represent a huge burden on public health. The results of Aim III will enhance our understanding of the mechanism of action of pathogenic mutations in FGFRs and other RTKs as well as the regulation of tyrosine kinase activity of the entire RTK superfamily. Since substrate recruitment and phosphorylation by RTKs is a general event in RTK signaling, the mechanistic insights gained under Aim IV will also be directly applicable to the entire RTK superfamily.

Public Health Relevance

Fibroblast growth factor (FGF) signaling plays essential roles in human development and metabolism, and when it goes awry it leads to a wide array of human diseases, including skeletal, olfactory reproductive syndromes, hearing loss, phosphate wasting disorders, neurodegenerative disorders, and cancer. The overall goal of this application is to elucidate the molecular basis for FGF signaling in development, metabolism, and disease. The proposed studies should not only enhance our understanding of the role of the FGF signaling in human physiology but also lay the foundations for the discovery of new drugs for the treatment of many major human diseases, which currently represent a huge burden on public health.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Macromolecular Structure and Function C Study Section (MSFC)
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Scholnick, Steven
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New York University
Schools of Medicine
New York
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Xu, C; Lang-Muritano, M; Phan-Hug, F et al. (2017) Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism. Clin Genet 92:213-216
Chen, Huaibin; Marsiglia, William M; Cho, Min-Kyu et al. (2017) Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases. Elife 6:
Liu, Yang; Ma, Jinghong; Beenken, Andrew et al. (2017) Regulation of Receptor Binding Specificity of FGF9 by an Autoinhibitory Homodimerization. Structure 25:1325-1336.e3
Huang, Chahua; Liu, Yang; Beenken, Andrew et al. (2017) A novel fibroblast growth factor-1 ligand with reduced heparin binding protects the heart against ischemia-reperfusion injury in the presence of heparin co-administration. Cardiovasc Res 113:1585-1602
Huang, Zhifeng; Marsiglia, William M; Basu Roy, Upal et al. (2016) Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase C?. Mol Cell 61:98-110
Fresco, Victor M; Kern, Christine B; Mohammadi, Moosa et al. (2016) Fibulin-1 Binds to Fibroblast Growth Factor 8 with High Affinity: EFFECTS ON EMBRYO SURVIVAL. J Biol Chem 291:18730-9
Liu, Yanlong; Zhao, Cuiqing; Xiao, Jian et al. (2016) Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury. Sci Rep 6:31026
Huang, Zhifeng; Tan, Li; Wang, Huiyan et al. (2015) DFG-out mode of inhibition by an irreversible type-1 inhibitor capable of overcoming gate-keeper mutations in FGF receptors. ACS Chem Biol 10:299-309
Zhao, Cuiqing; Liu, Yanlong; Xiao, Jian et al. (2015) FGF21 mediates alcohol-induced adipose tissue lipolysis by activation of systemic release of catecholamine in mice. J Lipid Res 56:1481-91
Barker, Sarah L; Pastor, Johanne; Carranza, Danielle et al. (2015) The demonstration of ?Klotho deficiency in human chronic kidney disease with a novel synthetic antibody. Nephrol Dial Transplant 30:223-33

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