Klotho converts canonical FGF receptor into a specific receptor for FGF23 (original) (raw)
- Letter
- Published: 29 October 2006
- Yuji Yamazaki1,
- Takashi Shimada1,
- Kousuke Iijima1,
- Hisashi Hasegawa1,
- Katsuya Okawa1,
- Toshiro Fujita2,
- Seiji Fukumoto2 &
- …
- Takeyoshi Yamashita1
Nature volume 444, pages 770–774 (2006)Cite this article
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Abstract
FGF23 is a unique member of the fibroblast growth factor (FGF) family because it acts as a hormone that derives from bone and regulates kidney functions, whereas most other family members are thought to regulate various cell functions at a local level1,2,3,4,5. The renotropic activity of circulating FGF23 indicates the possible presence of an FGF23-specific receptor in the kidney6. Here we show that a previously undescribed receptor conversion by Klotho, a senescence-related molecule7, generates the FGF23 receptor. Using a renal homogenate, we found that Klotho binds to FGF23. Forced expression of Klotho enabled the high-affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wild-type mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signalling, we searched for other components of the FGF23 receptor and found FGFR1(IIIc), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. These findings provide insights into the diversity and specificity of interactions between FGF and FGF receptors.
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Acknowledgements
We thank R. Imai, J. Murakami, M. Sato-Fujisawa, R. Hino, K. Sakuma, K. Ono and N. Yoshii for technical assistance, and Y. Nabeshima, T. Yoneya, T. Muto, T. Kawata, Y. Aono, J. Yasutake, N. Kasai and other members of our laboratories for advice and discussion. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, and from the Ministry of Health, Labour, and Welfare, Japan.
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- Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd, 3 Miyahara, Takasaki, Gunma, 370-1295, Japan
Itaru Urakawa, Yuji Yamazaki, Takashi Shimada, Kousuke Iijima, Hisashi Hasegawa, Katsuya Okawa & Takeyoshi Yamashita - Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
Toshiro Fujita & Seiji Fukumoto
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Correspondence toItaru Urakawa.
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Urakawa, I., Yamazaki, Y., Shimada, T. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23.Nature 444, 770–774 (2006). https://doi.org/10.1038/nature05315
- Received: 12 April 2006
- Accepted: 09 October 2006
- Published: 29 October 2006
- Issue Date: 07 December 2006
- DOI: https://doi.org/10.1038/nature05315
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Editorial Summary
Anti-ageing hormone
The klotho gene was first identified as a mutation in a mouse strain that exhibits a syndrome resembling human ageing, and overexpression of klotho extends the lifespan of mice. A possible mechanism of action for the Klotho protein has now been found: it converts FGFR1(IIIc), a receptor for various fibroblast growth factors acting at a local level, into a specific receptor for FGF23, a bone-derived hormone that regulates kidney function.