Fibroblast growth factor receptors display both common and distinct signaling pathways.
We compared the mitogenic and signaling pathways of three Fibroblast Growth Factor Receptors (FGFRs), FGFR1, KGFR and FGFR4 in the same cell line. Each receptor was expressed in L6E9 rat myoblasts that do not normally express detectable levels of FGFRs and clones that express comparable levels of each receptor were selected. Our results show that FGFs induce an effective survival and growth of FGFR1 and KGFR expressing cells. In addition, these cells exhibit a morphology that is reminiscent of that of malignantly transformed cells and display anchorage independent growth in a ligand dependent manner. Unlike KGFR and FGFR1, FGFR4 mediates a less effective growth, and cells overexpressing this receptor do not undergo any morphological changes nor do they display an anchorage independent growth in response to FGFs. All three receptors exhibit both quantitative and qualitative differences in their ability to induce tyrosine phosphorylation of cellular substrates. Both FGFR1 and KGFR induce strong phosphorylation of phospholipase C-gamma and a 90 kDa protein, while FGFR4 induces a relatively weak phosphorylation of phospholipase C-gamma and completely fails to induce phosphorylation of the 90 kDa. The three receptors also induce phosphorylation of the mitogen activated protein kinases (MAPK) but the effect of FGFR1 is far stronger than that of the other two receptors. Since FGFR4 is expressed in myoblasts in vivo, we examined whether this receptor can function in the differentiation pathway of myoblasts. Contrary to its weak mitogenic activity, FGFR4 effectively mediates the inhibition of myogenic differentiation in L6E9 cells and also suppresses the expression of the myogenic regulatory protein myogenin. Taken together, our results suggest that the signaling mechanism of FGFR4 differs from that of FGFR1 and KGFR, and that the primary role of FGFR4 in myoblasts may be the maintenance of their non differentiated state.
Shaoul
E
E
Department of Biology, Israel Institute of Technology, Technion City, Haifa.
Reich-Slotky
R
R
Berman
B
B
Ron
D
D
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D010738:Type C Phospholipases / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; D014443:Tyrosine; C496350:Fgfr1 protein, rat; C496373:Fgfr4 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051499:Receptor, Fibroblast Growth Factor, Type 4; C065104:keratinocyte growth factor receptor; D010738:Type C Phospholipases