Letter | Published:

Klotho converts canonical FGF receptor into a specific receptor for FGF23

Nature volume 444, pages 770774 (07 December 2006) | Download Citation



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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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.

Author information


  1. 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
  2. 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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Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Itaru Urakawa.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    Schematic illustration of the proposed FGF23-specific receptor that is composed of Klotho and FGFR1(IIIc).

  2. 2.

    Supplementary Figure 2

    The specific binding of FGF23 generated by Klotho.

  3. 3.

    Supplementary Figure 3

    Egr-1 protein was induced by FGF23 in Klotho-expressing Peak rapid cells.

  4. 4.

    Supplementary Figure 4

    Klotho-dependent Egr-1 reporter activation by diluted serum samples from Klotho deficient mice.

  5. 5.

    Supplementary Figure 5

    The FGFR1(IIIc)-Fc fusion protein specifically decreases FGF23 induced luciferase activity of the Egr-1 reporter.

  6. 6.

    Supplementary Figure 6

    Effects of GAGs on the FGF23 action.

Word documents

  1. 1.

    Supplementary Discussion

    This file contains an additional discussion of the findings of this paper.

  2. 2.

    Supplementary Tables

    This file contains Supplementary Tables 1–4.

  3. 3.

    Supplementary Methods

    This file contains additional details on the methods used in this study.

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