Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism.
OBJECTIVE
This review summarizes the most recent findings on Klotho in the regulation of fibroblast growth factor-23 (FGF23) signaling and phosphate/calcium homeostasis.


RESULTS
The klotho gene encodes a single-pass transmembrane protein and functions as an aging-suppressor gene, which extends life span when overexpressed and accelerates the development of aging-like phenotypes when disrupted in mice. FGF23 is a hormone that suppresses phosphate reabsorption in renal proximal tubules. Recent studies have shown that Klotho mice and Fgf23 mice exhibit identical phenotypes including hyperphosphatemia and hypercalcemia in addition to the aging-like syndrome. This may be explained by the fact that Klotho binds to multiple FGF receptors and increases their affinity to FGF23. Another Klotho protein function is to activate transient receptor potential vanilloid-5 - a calcium channel involved in calcium reabsorption in the kidney. Klotho protein can modify sugar chains on transient receptor potential vanilloid-5 through its activity as a beta-glucuronidase, preventing the calcium channel from internalization and inactivation.


CONCLUSIONS
Klotho protein binds to fibroblast growth factor receptors and functions as a regulator of FGF23 signaling. It also functions as an enzyme that modifies sugar chains of transient receptor potential vanilloid-5 and regulates its activity. Klotho is a multi-functional protein that regulates phosphate/calcium metabolism as well as aging.
Kuro-o
Makoto
M
Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072, USA. makoto.kuro-o@utsouthwestern.edu
D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000378:metabolism*; D005966:Glucuronidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D000090265:Klotho Proteins; D008659:Metabolic Diseases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010710:Phosphates / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D050916:TRPV Cation Channels; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium