Regulation of Fibroblast Growth Factor-23 Signaling by Klotho

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

doi:10.1074/jbc.c500457200

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.

Highlights

The Klotho gene encodes a 130-kDa single-pass transmembrane protein with a short cytoplasmic domain (10 amino acids) and is expressed predominantly in the kidney
To test the hypothesis that Klotho may be involved in FGF signaling, we investigated whether Klotho could directly bind to FGF receptors (FGFRs)
This may imply that Klotho affects the activity of multiple FGFs through binding to multiple FGFRs, the effect of Klotho on acidic and basic FGF was small when compared with its robust effect on Fibroblast growth factor-23 (FGF23)

Summary

Introduction

The Klotho gene encodes a 130-kDa single-pass transmembrane protein with a short cytoplasmic domain (10 amino acids) and is expressed predominantly in the kidney. (15), it has modest receptor affinity (KD ϭ 200 –700 nM) and often requires cofactors such as heparin or glycosaminoglycan [15, 16] to activate FGF signaling in cultured cells and to inhibit phosphate transport in proximal tubules perfused in vitro [13]. Klotho-deficient mice (KlothoϪ/Ϫ mice) and FGF23 deficient mice (Fgf23Ϫ/Ϫ mice) develop many common phenotypes, including shortened life span, growth retardation, infertility, muscle atrophy, hypoglycemia, and vascular calcification in the kidneys. They both have increased serum levels of phosphate [14, 17]. In this report we show that Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling activation by FGF23

Methods

Results

Conclusion