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Mol. Cell. Biol. 27 (9): 3417-3428

Copyright © 2007 by the American Society for Microbiology. All rights reserved.

Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of Fibroblast Growth Factor 19 Subfamily Members{triangledown}

Regina Goetz,1 Andrew Beenken,1 Omar A. Ibrahimi,1 Juliya Kalinina,1 Shaun K. Olsen,1 Anna V. Eliseenkova,1 ChongFeng Xu,1,7 Thomas A. Neubert,1 Fuming Zhang,2,7 Robert J. Linhardt,2 Xijie Yu,3 Kenneth E. White,3 Takeshi Inagaki,4 Steven A. Kliewer,4 Masaya Yamamoto,5 Hiroshi Kurosu,5 Yasushi Ogawa,5 Makoto Kuro-o,5 Beate Lanske,6 Mohammed S. Razzaque,6, and Moosa Mohammadi1*

Department of Pharmacology,1 Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016,7 Department of Chemistry, Biology, and Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180,2 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202,3 Department of Molecular Biology,4 Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd., Dallas, Texas 75390,5 Department of Oral and Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 021156

Received for publication 30 November 2006. Accepted for publication 15 February 2007.

Abstract: Unique among fibroblast growth factors (FGFs), FGF19, -21, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis. These FGFs require the presence of Klotho/ßKlotho in their target tissues. Here, we present the crystal structures of FGF19 alone and FGF23 in complex with sucrose octasulfate, a disaccharide chemically related to heparin. The conformation of the heparin-binding region between ß strands 10 and 12 in FGF19 and FGF23 diverges completely from the common conformation adopted by paracrine-acting FGFs. A cleft between this region and the ß1-ß2 loop, the other heparin-binding region, precludes direct interaction between heparin/heparan sulfate and backbone atoms of FGF19/23. This reduces the heparin-binding affinity of these ligands and confers endocrine function. Klotho/ßKlotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of FGF19, -21, and -23 to their cognate receptors.

* Corresponding author. Mailing address: Department of Pharmacology, New York University School of Medicine, New York, NY 10016. Phone: (212) 263-2907. Fax: (212) 263-7133. E-mail: mohammad{at}

{triangledown} Published ahead of print on 5 March 2007.

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Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands.
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Sulfated Glycosaminoglycans Are Required for Specific and Sensitive Fibroblast Growth Factor (FGF) 19 Signaling via FGF Receptor 4 and betaKlotho.
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J. Biol. Chem. 286, 26418-26423
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Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis.
E. M. Domouzoglou and E. Maratos-Flier (2011)
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Klotho Inhibits Transforming Growth Factor-{beta}1 (TGF-{beta}1) Signaling and Suppresses Renal Fibrosis and Cancer Metastasis in Mice.
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J. Biol. Chem. 286, 8655-8665
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J. Biochem. 149, 121-130
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K. Saxena, U. Schieborr, O. Anderka, E. Duchardt-Ferner, B. Elshorst, S. L. Gande, J. Janzon, D. Kudlinzki, S. Sreeramulu, M. K. Dreyer, et al. (2010)
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PNAS 107, 14158-14163
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Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation.
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Am J Physiol Endocrinol Metab 297, E1105-E1114
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Differential Interactions of FGFs with Heparan Sulfate Control Gradient Formation and Branching Morphogenesis.
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Homodimerization Controls the Fibroblast Growth Factor 9 Subfamily's Receptor Binding and Heparan Sulfate-Dependent Diffusion in the Extracellular Matrix.
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Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice.
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PNAS 106, 14379-14384
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Circulating Fibroblast Growth Factor-21 Is Elevated in Impaired Glucose Tolerance and Type 2 Diabetes and Correlates With Muscle and Hepatic Insulin Resistance.
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Diabetes Care 32, 1542-1546
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FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1.
J. Gattineni, C. Bates, K. Twombley, V. Dwarakanath, M. L. Robinson, R. Goetz, M. Mohammadi, and M. Baum (2009)
Am J Physiol Renal Physiol 297, F282-F291
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FGF21 induces PGC-1{alpha} and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response.
M. J. Potthoff, T. Inagaki, S. Satapati, X. Ding, T. He, R. Goetz, M. Mohammadi, B. N. Finck, D. J. Mangelsdorf, S. A. Kliewer, et al. (2009)
PNAS 106, 10853-10858
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Klotho in chronic kidney disease--What's new?.
M. Kuro-o (2009)
Nephrol. Dial. Transplant. 24, 1705-1708
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Initial FGF23-Mediated Signaling Occurs in the Distal Convoluted Tubule.
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J. Am. Soc. Nephrol. 20, 955-960
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FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action.
D.-J. Shin and T. F. Osborne (2009)
J. Biol. Chem. 284, 11110-11120
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FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player?.
M. S. Razzaque (2009)
Am J Physiol Renal Physiol 296, F470-F476
   Abstract »    Full Text »    PDF »
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 »
Does FGF23 toxicity influence the outcome of chronic kidney disease?.
M. S. Razzaque (2009)
Nephrol. Dial. Transplant. 24, 4-7
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Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice.
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Diabetes 58, 250-259
   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
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Klotho and Na+,K+-ATPase activity: solving the calcium metabolism dilemma?.
M. S. Razzaque (2008)
Nephrol. Dial. Transplant. 23, 459-461
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Co-receptor Requirements for Fibroblast Growth Factor-19 Signaling.
X. Wu, H. Ge, J. Gupte, J. Weiszmann, G. Shimamoto, J. Stevens, N. Hawkins, B. Lemon, W. Shen, J. Xu, et al. (2007)
J. Biol. Chem. 282, 29069-29072
   Abstract »    Full Text »    PDF »
Liver-specific Activities of FGF19 Require Klotho beta.
B. C. Lin, M. Wang, C. Blackmore, and L. R. Desnoyers (2007)
J. Biol. Chem. 282, 27277-27284
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Tissue-specific Expression of betaKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21.
H. Kurosu, M. Choi, Y. Ogawa, A. S. Dickson, R. Goetz, A. V. Eliseenkova, M. Mohammadi, K. P. Rosenblatt, S. A. Kliewer, and M. Kuro-o (2007)
J. Biol. Chem. 282, 26687-26695
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The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis.
M. S Razzaque and B. Lanske (2007)
J. Endocrinol. 194, 1-10
   Abstract »    Full Text »    PDF »

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