Klotho converts canonical FGF receptor into a specific receptor for FGF23.
FGF23 is a unique member of the fibroblast growth factor (FGF) family because it acts as a hormone that derives from bone and regulates kidney functions, whereas most other family members are thought to regulate various cell functions at a local level. The renotropic activity of circulating FGF23 indicates the possible presence of an FGF23-specific receptor in the kidney. Here we show that a previously undescribed receptor conversion by Klotho, a senescence-related molecule, generates the FGF23 receptor. Using a renal homogenate, we found that Klotho binds to FGF23. Forced expression of Klotho enabled the high-affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wild-type mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signalling, we searched for other components of the FGF23 receptor and found FGFR1(IIIc), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. These findings provide insights into the diversity and specificity of interactions between FGF and FGF receptors.
Urakawa
Itaru
I
Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd, 3 Miyahara, Takasaki, Gunma 370-1295, Japan. iurakawa@kirin.co.jp
Yamazaki
Yuji
Y
Shimada
Takashi
T
Iijima
Kousuke
K
Hasegawa
Hisashi
H
Okawa
Katsuya
K
Fujita
Toshiro
T
Fukumoto
Seiji
S
Yamashita
Takeyoshi
T
D000818:Animals; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity
D051766:Early Growth Response Protein 1; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins