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J. Biol. Chem. 281 (10): 6120-6123

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of Fibroblast Growth Factor-23 Signaling by Klotho*

Formula

Hiroshi Kurosu{ddagger}, Yasushi Ogawa{ddagger}, Masayoshi Miyoshi{ddagger}, Masaya Yamamoto{ddagger}, Animesh Nandi{ddagger}, Kevin P. Rosenblatt{ddagger}, Michel G. Baum§, Susan Schiavi, Ming-Chang Hu||, Orson W. Moe||, , and Makoto Kuro-o{ddagger}1

Department of {ddagger}Pathology, §Pediatrics, and ||Internal Medicine and Applied Genomics, Genzyme Corporation, The University of Texas Southwestern Medical Center, Dallas, Texas 75390

Abstract: The aging suppressor gene Klotho encodes a single-pass transmembrane protein. Klotho-deficient mice exhibit a variety of aging-like phenotypes, many of which are similar to those observed in fibroblast growth factor-23 (FGF23)-deficient mice. To test the possibility that Klotho and FGF23 may function in a common signal transduction pathway(s), we investigated whether Klotho is involved in FGF signaling. Here we show that Klotho protein directly binds to multiple FGF receptors (FGFRs). The Klotho-FGFR complex binds to FGF23 with higher affinity than FGFR or Klotho alone. In addition, Klotho significantly enhanced the ability of FGF23 to induce phosphorylation of FGF receptor substrate and ERK in various types of cells. Thus, Klotho functions as a cofactor essential for activation of FGF signaling by FGF23.


Received for publication November 28, 2005. Revision received January 18, 2006.

* This work was supported in part by grants from Endowed Scholar Program at the University of Texas Southwestern (to M. K.), Pew Scholars Program in Biomedical Science (to M. K.), Eisai Research Fund (to M. K.), High Impact/High Risk Research Program at The University of Texas Southwestern (to M. K.), The Ellison Medical Foundation (to M. K.), and by National Institutes of Health Grants R01AG19712 (to M. K.), R01AG25326 (to M. K. and K. P. R.), and R01DK065842 (to M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


Formula

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

1 To whom correspondence should be addressed: Dept. of Pathology, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd., Dallas, TX 75390-9072. Tel.: 214-648-4018; Fax: 214-648-4070; E-mail: makoto.kuroo{at}utsouthwestern.edu.


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In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis.
T. Nakatani, B. Sarraj, M. Ohnishi, M. J. Densmore, T. Taguchi, R. Goetz, M. Mohammadi, B. Lanske, and M. S. Razzaque (2009)
FASEB J 23, 433-441
   Abstract »    Full Text »    PDF »
FGFR3 and FGFR4 Do not Mediate Renal Effects of FGF23.
S. Liu, L. Vierthaler, W. Tang, J. Zhou, and L. D. Quarles (2008)
J. Am. Soc. Nephrol. 19, 2342-2350
   Abstract »    Full Text »    PDF »
C-terminal Tail of FGF19 Determines Its Specificity toward Klotho Co-receptors.
X. Wu, B. Lemon, X. Li, J. Gupte, J. Weiszmann, J. Stevens, N. Hawkins, W. Shen, R. Lindberg, J.-L. Chen, et al. (2008)
J. Biol. Chem. 283, 33304-33309
   Abstract »    Full Text »    PDF »
{beta}-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes.
J. Sinha, F. Chen, T. Miloh, R. C. Burns, Z. Yu, and B. L. Shneider (2008)
Am J Physiol Gastrointest Liver Physiol 295, G996-G1003
   Abstract »    Full Text »    PDF »
Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis.
H. J. Garringer, M. Malekpour, F. Esteghamat, S. M. J. Mortazavi, S. I. Davis, E. G. Farrow, X. Yu, D. E. Arking, H. C. Dietz, and K. E. White (2008)
Am J Physiol Endocrinol Metab 295, E929-E937
   Abstract »    Full Text »    PDF »
FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis.
D. Medici, M. S. Razzaque, S. DeLuca, T. L. Rector, B. Hou, K. Kang, R. Goetz, M. Mohammadi, M. Kuro-o, B. R. Olsen, et al. (2008)
J. Cell Biol. 182, 459-465
   Abstract »    Full Text »    PDF »
Pathophysiology of parathyroid hyperplasia in chronic kidney disease: preclinical and clinical basis for parathyroid intervention.
S. Goto, H. Komaba, and M. Fukagawa (2008)
Clinical Kidney Journal 1, iii2-iii8
   Abstract »    Full Text »    PDF »
Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1.
S.-K. Cha, B. Ortega, H. Kurosu, K. P. Rosenblatt, M. Kuro-o, and C.-L. Huang (2008)
PNAS 105, 9805-9810
   Abstract »    Full Text »    PDF »
A translocation causing increased {alpha}-Klotho level results in hypophosphatemic rickets and hyperparathyroidism.
C. A. Brownstein, F. Adler, C. Nelson-Williams, J. Iijima, P. Li, A. Imura, Y.-i. Nabeshima, M. Reyes-Mugica, T. O. Carpenter, and R. P. Lifton (2008)
PNAS 105, 3455-3460
   Abstract »    Full Text »    PDF »
Postprandial Mineral Metabolism and Secondary Hyperparathyroidism in Early CKD.
T. Isakova, O. Gutierrez, A. Shah, L. Castaldo, J. Holmes, H. Lee, and M. Wolf (2008)
J. Am. Soc. Nephrol. 19, 615-623
   Abstract »    Full Text »    PDF »
Distinct roles for intrinsic osteocyte abnormalities and systemic factors in regulation of FGF23 and bone mineralization in Hyp mice.
S. Liu, W. Tang, J. Zhou, L. Vierthaler, and L. D. Quarles (2007)
Am J Physiol Endocrinol Metab 293, E1636-E1644
   Abstract »    Full Text »    PDF »

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