Regulation of Fibroblast Growth Factor-23 Signaling by Klotho

TLDR

Klotho is an aging‑suppression transmembrane protein whose deficiency produces aging‑like phenotypes that mirror those seen in FGF23‑deficient mice. The study aimed to determine whether Klotho participates in FGF signaling pathways. The authors investigated Klotho’s role by examining its interactions with FGFRs and FGF23. Klotho directly binds multiple FGFRs, forming a complex that binds FGF23 with higher affinity and markedly enhances FGF23‑induced phosphorylation of FRS2 and ERK, establishing Klotho as an essential cofactor for FGF23‑mediated FGF signaling.

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.