FGF-21/FGF-21 receptor interaction and activation is determined by betaKlotho.
Fibroblast growth factor-21 (FGF-21) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that betaKlotho is an integral part of an activated FGF-21-betaKlotho-FGF receptor (FGFR) complex thus a critical subunit of the FGF-21 receptor. Cells lacking betaKlotho did not respond to FGF-21; the introduction of betaKlotho to these cells conferred FGF-21-responsiveness and recapitulated the entire scope of FGF-21 signaling observed in naturally responsive cells. Interestingly, FGF-21-mediated effects are heparin independent suggesting that betaKlotho plays a role in FGF-21 activity similar to the one played by heparin in the signaling of conventional FGFs. Moreover, in addition to conferring specificity for FGF-21, betaKlotho appears to support FGF-19 activity and mediates the receptor selectivity profile of FGF-19. All together, these results indicate that betaKlotho and FGFRs form the cognate FGF-21 receptor complex, mediating FGF-21 cellular specificity and physiological effects.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. a.kharch@lilly.com
Alexei
A
Kharitonenkov
James D
JD
Dunbar
Holly A
HA
Bina
Stuart
S
Bright
Julie S
JS
Moyers
Chen
C
Zhang
Liyun
L
Ding
Radmila
R
Micanovic
Sean F
SF
Mehrbod
Michael D
MD
Knierman
John E
JE
Hale
Tamer
T
Coskun
Armen B
AB
Shanafelt
D041721:3T3-L1 Cells; D000818:Animals; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*
C418622:Klb protein, mouse; D008565:Membrane Proteins; D017468:Receptors, Fibroblast Growth Factor; C414620:fibroblast growth factor 21; C526616:fibroblast growth factor-21 receptor, mouse; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins