Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation
Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation
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DOI：
10.1073/pnas.1815166116
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发表时间：
2019-06-04
影响因子：
11.1
通讯作者：
Fukumoto, Seiji
中科院分区：
文献类型：
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作者：
Takashi, Yuichi;Kosako, Hidetaka;Fukumoto, Seiji
成纤维细胞生长因子（FGF） 23由骨骼产生，是一种降低血清磷酸盐（Pi）的激素。血清FGF23受血清Pi变化的严格调节，反映了其在Pi控制中的核心作用。FGF23水平受转录事件和翻译后裂解成无活性片段的调控。对于后者，GALNT3基因产物对FGF23的o -糖基化阻止了裂解，导致血清FGF23升高。然而，Pi感测在血清FGF23调控中的分子基础尚不清楚。在这项研究中，我们发现高Pi饮食增强了Galnt3的骨骼表达，而不是Fgf23，预计小鼠血清Fgf23和Pi会增加。在成骨细胞UMR 106中进一步观察到高Pi诱导Galnt3，这是通过激活细胞外信号调节激酶（ERK）途径介导的。通过对高Pi上游传感器的蛋白质组学搜索，我们确定了FGF受体（FGFR1c）的一种亚型，该亚型在没有FGF的情况下被高Pi磷酸化。当监测FGFR底物2 α和ERK的磷酸化时，高Pi激活未配体FGFR的模式似乎不同于与典型FGFR配体（FGF2）结合的FGFR。最后，我们发现FGFR抑制剂和成骨细胞/骨细胞中Fgfr1的条件缺失消除了高Pi饮食诱导的小鼠血清FGF23和股骨Galnt3表达的增加。因此，这些发现揭示了未配体FGFR功能的一个未被认识的方面，并阐明了参与调节FGF23产生的pi感应途径。
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 post-translational 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 2 alpha 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.