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J Biol Chem. 2006 Mar 10;281(10):6120-3. Epub 2006 Jan 25.

Regulation of fibroblast growth factor-23 signaling by klotho.

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Department of Pathology, Pediatrics, and Internal Medicine and Applied Genomics, Genzyme Corporation, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.


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.

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