FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho

Fibroblast growth factor-21 (FGF-2 1) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that beta Klotho is an integral part of an activated FGF-21-beta Klotho-FGF receptor (FGFR) complex thus a critical subunit of the FGF-21 receptor. Cells lacking beta Klotho did not respond to FGF-21; the introduction of PKIotho 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 beta Klotho 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-2 1, beta Klotho appears to support FGF-19 activity and mediates the receptor selectivity profile of FGF-19. All together, these results indicate that beta Klothoand FGFRs form the cognate FGF-21 receptor complex, mediating FGF-21 cellular specificity and physiological effects.