Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor.
FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Regina
R
Goetz
Mutsuko
M
Ohnishi
Serkan
S
Kir
Hiroshi
H
Kurosu
Lei
L
Wang
Johanne
J
Pastor
Jinghong
J
Ma
Weiming
W
Gai
Makoto
M
Kuro-o
Mohammed S
MS
Razzaque
Moosa
M
Mohammadi
D000818:Animals; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D004703:Endocrine System / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D019899:Paracrine Communication; D015398:Signal Transduction
D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse