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

Research output: Contribution to journalArticle

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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
StatePublished - Aug 17 2012

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Heparitin Sulfate
Fibroblast Growth Factors
Ligands
Lipid Metabolism
Sulfates
Homeostasis
Obesity
Phosphates
Binding Sites
Cells
Hormones
Tissue
Glucose
Molecules
fibroblast growth factor 21

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

Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. / Goetz, Regina; Ohnishi, Mutsuko; Kir, Serkan; Kurosu, Hiroshi; Wang, Lei; Pastor, Johanne; Ma, Jinghong; Gai, Weiming; Kuro-o, Makoto; Razzaque, Mohammed S.; Mohammadi, Moosa.

In: Journal of Biological Chemistry, Vol. 287, No. 34, 17.08.2012, p. 29134-29146.

Research output: Contribution to journalArticle

Goetz, R, Ohnishi, M, Kir, S, Kurosu, H, Wang, L, Pastor, J, Ma, J, Gai, W, Kuro-o, M, Razzaque, MS & Mohammadi, M 2012, 'Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor', Journal of Biological Chemistry, vol. 287, no. 34, pp. 29134-29146. https://doi.org/10.1074/jbc.M112.342980
Goetz, Regina ; Ohnishi, Mutsuko ; Kir, Serkan ; Kurosu, Hiroshi ; Wang, Lei ; Pastor, Johanne ; Ma, Jinghong ; Gai, Weiming ; Kuro-o, Makoto ; Razzaque, Mohammed S. ; Mohammadi, Moosa. / Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 34. pp. 29134-29146.
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