title: Sulfated glycosaminoglycans are required for specific and sensitive fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and betaKlotho.
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.
authors.affiliation: Signaling Molecules Research Group, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8566, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Uehara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asada
authors.forename: Emi
authors.initials: E
authors.lastname: Honda
authors.forename: Naoko
authors.initials: N
authors.lastname: Nagai
authors.forename: Koji
authors.initials: K
authors.lastname: Kimata
authors.forename: Masashi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Toru
authors.initials: T
authors.lastname: Imamura
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: C117476:FGF19 protein, human; D006025:Glycosaminoglycans; C538995:KLB protein, human; D008565:Membrane Proteins; C013786:A73025; D005346:Fibroblast Growth Factors; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000090265:Klotho Proteins