Co-receptor requirements for fibroblast growth factor-19 signaling.
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.
Wu
Xinle
X
Amgen Inc., South San Francisco, California 94080, USA.
Ge
Hongfei
H
Gupte
Jamila
J
Weiszmann
Jennifer
J
Shimamoto
Grant
G
Stevens
Jennitte
J
Hawkins
Nessa
N
Lemon
Bryan
B
Shen
Wenyan
W
Xu
Jing
J
Veniant
Murielle M
MM
Li
Yue-Sheng
YS
Lindberg
Richard
R
Chen
Jin-Long
JL
Tian
Hui
H
Li
Yang
Y
D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004703:Endocrine System / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000502:physiology*; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D014162:Transfection
D017077:Culture Media, Conditioned; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D006497:Heparan Sulfate; D000090265:Klotho Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C117476:FGF19 protein, human