Conversion of a Paracrine Fibroblast Growth Factor into an Endocrine Fibroblast Growth Factor

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2012 Jun 27

PMID 22733815

Citations 47

Authors

Regina Goetz

Mutsuko Ohnishi

Serkan Kir

Hiroshi Kurosu

Lei Wang

Johanne Pastor

Jinghong Ma

Weiming Gai

Makoto Kuro-O

Mohammed S Razzaque

Moosa Mohammadi

Affiliations

Soon will be listed here.

Abstract

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.

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