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Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11418-11427. doi: 10.1073/pnas.1815166116. Epub 2019 May 16.

Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation.

Author information

1
Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 7708503 Tokushima, Japan.
2
Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 7708503 Tokushima, Japan.
3
Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Bunkyo-ku, 1138655 Tokyo, Japan.
4
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 7708503 Tokushima, Japan.
5
Graduate School of Science and Engineering, Iryo Sosei University, Iwaki, 9708551 Fukushima, Japan.
6
Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki, 9728322 Fukushima, Japan.
7
Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 7708503 Tokushima, Japan; fukumoto-tky@umin.ac.jp.

Abstract

Fibroblast growth factor (FGF) 23 produced by bone is a hormone that decreases serum phosphate (Pi). Reflecting its central role in Pi control, serum FGF23 is tightly regulated by serum Pi alterations. FGF23 levels are regulated by the transcriptional event and posttranslational cleavage into inactive fragments before its secretion. For the latter, O-glycosylation of FGF23 by GALNT3 gene product prevents the cleavage, leading to an increase in serum FGF23. However, the molecular basis of Pi sensing in the regulation of serum FGF23 remains elusive. In this study, we showed that high Pi diet enhanced the skeletal expression of Galnt3, but not Fgf23, with expected increases in serum FGF23 and Pi in mice. Galnt3 induction by high Pi was further observed in osteoblastic UMR 106 cells, and this was mediated by activation of the extracellular signal-regulated kinase (ERK) pathway. Through proteomic searches for the upstream sensor for high Pi, we identified one subtype of the FGF receptor (FGFR1c), which was phosphorylated by high Pi in the absence of FGFs. The mode of unliganded FGFR activation by high Pi appeared different from that of FGFR bound to a canonical FGFR ligand (FGF2) when phosphorylation of the FGFR substrate 2α and ERK was monitored. Finally, we showed that an FGFR inhibitor and conditional deletion of Fgfr1 in osteoblasts/osteocytes abrogated high Pi diet-induced increases in serum FGF23 and femoral Galnt3 expression in mice. Thus, these findings uncover an unrecognized facet of unliganded FGFR function and illustrate a Pi-sensing pathway involved in regulation of FGF23 production.

KEYWORDS:

fibroblast growth factor 23; fibroblast growth factor receptor 1; phosphate sensor

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