Abstract
FGF19 is a unique member of the fibroblast growth factor (FGF) family of secreted proteins that regulates bile acid homeostasis and metabolic state in an endocrine fashion. Here we investigate the cell surface receptors required for signaling by FGF19. We show that betaKlotho, a single-pass transmembrane protein highly expressed in liver and fat, induced ERK1/2 phosphorylation in response to FGF19 treatment and significantly increased the interactions between FGF19 and FGFR4. Interestingly, our results show that alphaKlotho, another Klotho family protein related to betaKlotho, also induced ERK1/2 phosphorylation in response to FGF19 treatment and increased FGF19-FGFR4 interactions in vitro, similar to the effects of betaKlotho. In addition, heparin further enhanced the effects of both alphaKlotho and betaKlotho in FGF19 signaling and interaction experiments. These results suggest that a functional FGF19 receptor may consist of FGF receptor (FGFR) and heparan sulfate complexed with either alphaKlotho or betaKlotho.
Highlights
The fibroblast growth factors (FGFs)2 constitute a structurally related family of 22 proteins [1]
Klotho and Heparin Enhance FGF19 Activation of FGF receptor (FGFR) Signaling—Since Klotho is highly expressed in the liver and mice deficient in Klotho exhibit a dramatic elevation of bile acid synthesis, we tested the possibility that Klotho might function as a co-receptor for FGF19
We used a luciferase reporter assay system based on ERK1/2 phosphorylation [22] to test the activation of the FGF signaling pathway by FGF19 in HEK293 cells, which normally do not respond to FGF19 treatment
Summary
The fibroblast growth factors (FGFs)2 constitute a structurally related family of 22 proteins [1]. ACCELERATED PUBLICATION: Receptor Requirements for FGF19 together with relatively high concentrations of heparin confers the strongest binding of FGF19 to FGFR and results in the highest level of ERK1/2 phosphorylation following receptor activation. We used a luciferase reporter assay system based on ERK1/2 phosphorylation [22] to test the activation of the FGF signaling pathway by FGF19 in HEK293 cells, which normally do not respond to FGF19 treatment.
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