| Item type |
文献 / Documents(1) |
| 公開日 |
2019-09-03 |
| アクセス権 |
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|
アクセス権 |
open access |
| 資源タイプ |
|
|
資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
|
資源タイプ |
journal article |
| 出版社版DOI |
|
|
|
識別子タイプ |
DOI |
|
|
関連識別子 |
https://doi.org/10.1073/pnas.1815166116 |
|
|
言語 |
ja |
|
|
関連名称 |
10.1073/pnas.1815166116 |
| 出版タイプ |
|
|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
|
|
タイトル |
Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation |
|
言語 |
en |
| 著者 |
髙士, 祐一
小迫, 英尊
沢津橋, 俊
キノシタ, ユカ
イトウ, ノブアキ
Tsoumpra, Maria K.
ナンガク, マサオミ
安倍, 正博
松久, 宗英
カトウ, シゲアキ
松本, 俊夫
福本, 誠二
|
| 抄録 |
|
|
内容記述タイプ |
Abstract |
|
内容記述 |
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. |
|
言語 |
en |
| 書誌情報 |
en : Proceedings of the National Academy of Sciences of the United States of America
巻 116,
号 23,
p. 11418-11427,
発行日 2019-05-16
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| 収録物ID |
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収録物識別子タイプ |
ISSN |
|
収録物識別子 |
00278424 |
| 収録物ID |
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収録物識別子タイプ |
ISSN |
|
収録物識別子 |
10916490 |
| 収録物ID |
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収録物識別子タイプ |
NCID |
|
収録物識別子 |
AA11726874 |
| 出版者 |
|
|
出版者 |
National Academy of Sciences |
|
言語 |
en |
| 権利情報 |
|
|
言語 |
en |
|
権利情報 |
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). |
| EID |
|
|
識別子 |
352089 |
|
識別子タイプ |
URI |
| 言語 |
|
|
言語 |
eng |
pnas_116_23_11418.pdf (2.03 MB)
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