RRC ID 18602
Author Nakamura M, Uehara Y, Asada M, Honda E, Nagai N, Kimata K, Suzuki M, Imamura T.
Title Sulfated glycosaminoglycans are required for specific and sensitive fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and betaKlotho.
Journal J Biol Chem
Abstract Secreted from intestine, human fibroblast growth factor 19 (hFGF19) is an endocrine metabolic regulator that controls bile acid synthesis in the liver. Earlier studies have suggested that hFGF19 at 10-100 nM levels signals through FGF receptor 4 (FGFR4) in the presence of a co-receptor, betaKlotho, but its activity and receptor specificity at physiological concentrations (picomolar levels) remain unclear. Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. Importantly, sGAGs isolated from liver are highly active in enhancing the picomolar hFGF19 signaling. At nanomolar levels, in contrast, hFGF19 activates all types of human FGFRs, i.e. FGFR1c, FGFR2c, FGFR3c, and FGFR4 in the co-presence of betaKlotho and heparin and activates FGFR4 even in the absence of betaKlotho. These results show that sGAGs play crucial roles in specific and sensitive hFGF19 signaling via FGF receptors and suggest that hepatic sGAGs are involved in the highly potent and specific signaling of picomolar hFGF19 through FGFR4 and betaKlotho. The results further suggest that hFGF19 at pathological concentrations may evoke aberrant signaling through various FGF receptors.
Volume 286(30)
Pages 26418-23
Published 2011-7-29
DOI 10.1074/jbc.M111.251140
PII S0021-9258(19)48462-7
PMID 21653700
PMC PMC3143605
MeSH Animals Cattle Cell Line Fibroblast Growth Factors / genetics Fibroblast Growth Factors / metabolism* Glycosaminoglycans / chemistry Glycosaminoglycans / isolation & purification Glycosaminoglycans / metabolism* Glycosaminoglycans / pharmacology Humans Klotho Proteins Liver / metabolism* Membrane Proteins / genetics Membrane Proteins / metabolism* Receptor, Fibroblast Growth Factor, Type 4 / genetics Receptor, Fibroblast Growth Factor, Type 4 / metabolism* Signal Transduction / drug effects Signal Transduction / physiology*
IF 4.238
Times Cited 15
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Human and Animal Cells Ba/F3(RCB0805)