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J Biol Chem. 2015 Apr 17;290(16):10447-59. doi: 10.1074/jbc.M114.609230. Epub 2015 Mar 9.

Membrane and integrative nuclear fibroblastic growth factor receptor (FGFR) regulation of FGF-23.

Author information

1
From the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
2
From the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163 dquarles@uthsc.edu.

Abstract

Fibroblastic growth factor receptor 1 (FGFR1) signaling pathways are implicated in the regulation of FGF-23 gene transcription, but the molecular pathways remain poorly defined. We used low molecular weight (LMW, 18 kDa) FGF-2 and high molecular weight (HMW) FGF-2 isoforms, which, respectively, activate cell surface FGF receptors and intranuclear FGFR1, to determine the roles of membrane FGFRs and integrative nuclear FGFR1 signaling (INFS) in the regulation of FGF-23 gene transcription in osteoblasts. We found that LMW-FGF-2 induced NFAT and Ets1 binding to conserved cis-elements in the proximal FGF-23 promoter and stimulated FGF-23 promoter activity through PLCγ/calcineurin/NFAT and MAPK pathways in SaOS-2 and MC3T3-E1 osteoblasts. In contrast, HMW-FGF-2 stimulated FGF-23 promoter activity in osteoblasts through a cAMP-dependent binding of FGFR1 and cAMP-response element-binding protein (CREB) to a conserved cAMP response element (CRE) contiguous with the NFAT binding site in the FGF-23 promoter. Mutagenesis of the NFAT and CRE binding sites, respectively, inhibited the effects of LMW-FGF-2 and HMW-FGF-23 to stimulate FGF-23 promoter activity. FGF-2 activation of both membrane FGFRs and INFS-dependent FGFR1 pathways may provide a means to integrate systemic and local regulation of FGF-23 transcription under diverse physiological and pathological conditions.

KEYWORDS:

Calcineurin; Cyclic AMP (cAMP); Fibroblast Growth Factor (FGF); Fibroblast Growth Factor Receptor (FGFR); Osteoblast

PMID:
25752607
PMCID:
PMC4400353
DOI:
10.1074/jbc.M114.609230
[Indexed for MEDLINE]
Free PMC Article

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