Sulfated glycosaminoglycan-assisted receptor specificity of human fibroblast growth factor (FGF) 19 signaling in a mouse system is different from that in a human system.
The endocrine action of human (h) intestine-derived fibroblast growth factor 19 (hFGF19) toward liver cells necessitates a highly specific recognition system. We previously reported that at physiological concentrations (~30 pM), hFGF19 requires sulfated glycosaminoglycans (sGAGs) for its signaling via human FGF receptor 4 (hFGFR4) in the presence of a co-receptor, human βKlotho (hKLB), thus establishing specific targeting. Here we report that the specificity of hFGF19 signaling is greatly altered in a mouse model system. In in vitro cellular systems, at concentrations achievable in transgenic animals and in pharmacologic animal experiments (1-100 nM), hFGF19 activates mouse (m)FGFR1c, mFGFR2c, and mFGFR3c but not mFGFR4 in the presence of mKLB and nonheparin authentic sGAGs. Furthermore, in the presence of hepatic sGAGs or heparin, nanomolar hFGF19 activates mFGFR4, even in the absence of co-expressed mKLB. Taken together, these results indicate that the sGAG-assisted receptor specificity of hFGF19 signaling achieved in experimental mouse systems differs greatly from that in physiological human systems. This suggests the function and mechanism of hFGF19 signaling identified using mouse systems should be reevaluated.
National Institute of Advanced Industrial Science and Technology AIST, Tsukuba, Ibaraki 305-8566, Japan.
Masao
M
Nakamura
Yuriko
Y
Uehara
Masahiro
M
Asada
Masashi
M
Suzuki
Toru
T
Imamura
D000818:Animals; D045744:Cell Line, Tumor; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction
C117476:FGF19 protein, human; D011956:Receptors, Cell Surface; C086020:glycosaminoglycan receptor; D005346:Fibroblast Growth Factors; D006493:Heparin; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4