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

Regina Goetz, Mutsuko Ohnishi, Serkan Kir, Hiroshi Kurosu, Lei Wang, Johanne Pastor, Jinghong Ma, Weiming Gai, Makoto Kuro-o, Mohammed S. Razzaque, Moosa Mohammadi

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Abstract

FGFs 19, 21, and 23 are hormones that regulate in a Klothoco-receptor- dependent fashion major metabolic processes suchas glucose and lipid metabolism (FGF21) and phosphate andvitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycanin the formation of the cell surface signalingcomplex of endocrine FGFs has remained unclear. Here we showthat heparan sulfate is not a component of the signal transductionunit of FGF19 and FGF23. In support of our model, weconvert a paracrine FGF into an endocrine ligand by diminishingheparan sulfate-binding affinity of the paracrine FGF andsubstituting its C-terminal tail for that of an endocrine FGF containingthe Klotho co-receptor-binding site to home the ligandinto the target tissue. In addition to serving as a proof of concept,the ligand conversion provides a novel strategy for engineeringendocrine FGF-like molecules for the treatment of metabolicdisorders, including global epidemics such as type 2 diabetesand obesity.

Original languageEnglish (US)
Pages (from-to)29134-29146
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number34
DOIs
Publication statusPublished - Aug 17 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Goetz, R., Ohnishi, M., Kir, S., Kurosu, H., Wang, L., Pastor, J., ... Mohammadi, M. (2012). Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. Journal of Biological Chemistry, 287(34), 29134-29146. https://doi.org/10.1074/jbc.M112.342980