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Fibroblast growth factor receptors display both common and distinct signaling pathways
E Shaoul1, R Reich-Slotky, B Berman
1Department of Biology, Israel Institute of Technology, Technion City, Haifa.
Abstract:
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.
Insights
Fibroblast Growth Factor Receptors (FGFRs) 1 and KGFR promote cell growth and transformation, while FGFR4 inhibits myoblast differentiation. Signaling pathways differ significantly among these receptors.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- Fibroblast Growth Factor Receptors (FGFRs) are crucial for cell growth and differentiation.
- Understanding the specific roles of different FGFRs in various cell types is essential for comprehending developmental and disease processes.
Purpose of the Study:
- To compare the mitogenic and signaling pathways of FGFR1, KGFR, and FGFR4 in L6E9 rat myoblasts.
- To investigate the distinct functional roles of FGFR4 in myoblast differentiation.
Main Methods:
- Expression of FGFR1, KGFR, and FGFR4 in L6E9 rat myoblasts.
- Analysis of cell proliferation, morphology, anchorage-independent growth, and substrate phosphorylation.
- Assessment of FGFR4's effect on myogenic differentiation and myogenin expression.
Main Results:
- FGFR1 and KGFR expression promoted cell survival, growth, and anchorage-independent growth, with morphological changes resembling malignant transformation.
- FGFR4 exhibited weaker mitogenic effects and did not induce morphological changes or anchorage-independent growth.
- Differential tyrosine phosphorylation patterns were observed for phospholipase C-gamma, a 90 kDa protein, and mitogen-activated protein kinases (MAPK) among the three receptors.
- FGFR4 effectively inhibited myogenic differentiation and suppressed myogenin expression, despite its limited mitogenic activity.
Conclusions:
- FGFR4 possesses distinct signaling mechanisms compared to FGFR1 and KGFR.
- FGFR4's primary role in myoblasts appears to be maintaining their undifferentiated state by inhibiting differentiation.