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Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2012
Author Goetz R, Ohnishi M, Kir S, Kurosu H, Wang L, Pastor J, Ma J, Gai W, Kuro-o M, Razzaque MS, Mohammadi M,
Project FGF21 is a link between reproduction and energy balance
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Original article (peer-reviewed)

Journal Journal of Biological Chemistry
Volume (Issue) 287(34)
Page(s) 29134 - 29146
Title of proceedings Journal of Biological Chemistry
DOI 10.1074/jbc.M112.342980


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