Regulation of fibroblast growth factor-23 signaling by klotho.
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ABSTRACT:
SUBMITTER: Kurosu H
PROVIDER: S-EPMC2637204 | biostudies-literature | 2006 Mar
REPOSITORIES: biostudies-literature
Publications
Regulation of fibroblast growth factor-23 signaling by klotho.
Kurosu Hiroshi H Ogawa Yasushi Y Miyoshi Masayoshi M Yamamoto Masaya M Nandi Animesh A Rosenblatt Kevin P KP Baum Michel G MG Schiavi Susan S Hu Ming-Chang MC Moe Orson W OW Kuro-o Makoto M
The Journal of biological chemistry 20060125 10
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 ...[more]
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Project description:It has been recently established that Klotho coreceptors associate with fibroblast growth factor (FGF) receptor tyrosine kinases (FGFRs) to enable signaling by endocrine-acting FGFs. However, the molecular interactions leading to FGF-FGFR-Klotho ternary complex formation remain incompletely understood. Here, we show that in contrast to αKlotho, βKlotho binds its cognate endocrine FGF ligand (FGF19 or FGF21) and FGFR independently through two distinct binding sites. FGF19 and FGF21 use their respective C-terminal tails to bind to a common binding site on βKlotho. Importantly, we also show that Klotho coreceptors engage a conserved hydrophobic groove in the immunoglobulin-like domain III (D3) of the "c" splice isoform of FGFR. Intriguingly, this hydrophobic groove is also used by ligands of the paracrine-acting FGF8 subfamily for receptor binding. Based on this binding site overlap, we conclude that while Klotho coreceptors enhance binding affinity of FGFR for endocrine FGFs, they actively suppress binding of FGF8 subfamily ligands to FGFR.
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