The Klotho gene encodes a single-pass transmembrane protein with a short cytoplasmic domain, primarily expressed in the kidney. Klotho-deficient mice exhibit aging-like phenotypes, including shortened lifespan, skin atrophy, muscle atrophy, osteoporosis, and vascular calcification, similar to those observed in FGF23-deficient mice. These findings suggest that Klotho and FGF23 may function in a common signaling pathway. The study shows that Klotho directly binds to multiple FGF receptors (FGFRs) and enhances the ability of FGF23 to induce phosphorylation of FGF receptor substrates and ERK in various cell types. The Klotho-FGFR complex binds FGF23 with higher affinity than FGFR or Klotho alone, indicating that Klotho functions as a cofactor essential for FGF23 signaling activation. Klotho is a glycoprotein that is shed and secreted into the blood, potentially functioning as a humoral factor that suppresses intracellular insulin/IGF1 signaling. However, the signaling pathway(s) directly activated by Klotho, including the identity of the Klotho receptor, remains to be determined. FGF23, originally identified as a gene mutated in patients with autosomal dominant hypophosphatemic rickets, inhibits phosphate transport in renal proximal tubular cells and in vitro perfused proximal tubules. FGF23 binds to multiple FGFRs but has modest receptor affinity and often requires cofactors such as heparin or glycosaminoglycan to activate FGF signaling. The study demonstrates that Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling activation by FGF23. Klotho-deficient mice and FGF23-deficient mice develop many common phenotypes, including shortened lifespan, growth retardation, infertility, muscle atrophy, hypoglycemia, and vascular calcification in the kidneys. Both have increased serum levels of phosphate, supporting the hypothesis that Klotho and FGF23 may function via a common signal transduction pathway. The results indicate that Klotho enhances the cellular sensitivity to FGF23, suggesting that it may function as a paracrine factor in the kidney. The study also shows that Klotho can function as a regulator of FGF23 signaling in various cell types, including non-kidney cells. The findings suggest that Klotho may affect the activity of multiple FGFs through binding to multiple FGFRs.The Klotho gene encodes a single-pass transmembrane protein with a short cytoplasmic domain, primarily expressed in the kidney. Klotho-deficient mice exhibit aging-like phenotypes, including shortened lifespan, skin atrophy, muscle atrophy, osteoporosis, and vascular calcification, similar to those observed in FGF23-deficient mice. These findings suggest that Klotho and FGF23 may function in a common signaling pathway. The study shows that Klotho directly binds to multiple FGF receptors (FGFRs) and enhances the ability of FGF23 to induce phosphorylation of FGF receptor substrates and ERK in various cell types. The Klotho-FGFR complex binds FGF23 with higher affinity than FGFR or Klotho alone, indicating that Klotho functions as a cofactor essential for FGF23 signaling activation. Klotho is a glycoprotein that is shed and secreted into the blood, potentially functioning as a humoral factor that suppresses intracellular insulin/IGF1 signaling. However, the signaling pathway(s) directly activated by Klotho, including the identity of the Klotho receptor, remains to be determined. FGF23, originally identified as a gene mutated in patients with autosomal dominant hypophosphatemic rickets, inhibits phosphate transport in renal proximal tubular cells and in vitro perfused proximal tubules. FGF23 binds to multiple FGFRs but has modest receptor affinity and often requires cofactors such as heparin or glycosaminoglycan to activate FGF signaling. The study demonstrates that Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling activation by FGF23. Klotho-deficient mice and FGF23-deficient mice develop many common phenotypes, including shortened lifespan, growth retardation, infertility, muscle atrophy, hypoglycemia, and vascular calcification in the kidneys. Both have increased serum levels of phosphate, supporting the hypothesis that Klotho and FGF23 may function via a common signal transduction pathway. The results indicate that Klotho enhances the cellular sensitivity to FGF23, suggesting that it may function as a paracrine factor in the kidney. The study also shows that Klotho can function as a regulator of FGF23 signaling in various cell types, including non-kidney cells. The findings suggest that Klotho may affect the activity of multiple FGFs through binding to multiple FGFRs.