Membrane and integrative nuclear fibroblastic growth factor receptor (FGFR) regulation of FGF-23.
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.
From the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Xiaobin
X
Han
From the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Zhousheng
Z
Xiao
From the Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163 dquarles@uthsc.edu.
L Darryl
LD
Quarles
D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008970:Molecular Weight; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D050784:Proto-Oncogene Protein c-ets-1; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C494041:ETS1 protein, human; C000717427:FGF23 protein, human; D050778:NFATC Transcription Factors; D020033:Protein Isoforms; D050784:Proto-Oncogene Protein c-ets-1; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D000242:Cyclic AMP; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin; D051966:Phospholipase C gamma
Calcineurin; Cyclic AMP (cAMP); Fibroblast Growth Factor (FGF); Fibroblast Growth Factor Receptor (FGFR); Osteoblast