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Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1
S Vainikka1, V Joukov, S Wennström
1Department of Pathology, University of Helsinki, Finland.
Abstract:
We have studied the signal transduction pathways of fibroblast growth factor receptor-4 (FGFR-4) and FGFR-1, which showed virtually identical acidic fibroblast growth factor binding profiles as well as tyrosine autophosphorylation upon activation in transfected L6 rat myoblasts and NIH3T3 mouse fibroblasts. A prominently tyrosyl-phosphorylated doublet of polypeptides of 85 kDa coprecipitated with activated FGFR-4 from both cell lines studied, but these polypeptides were not detected upon immunoprecipitation of activated FGFR-1. Furthermore, FGFR-4 induced only a weak tyrosyl phosphorylation of phospholipase C-gamma and no detectable tyrosyl phosphorylation of the SHC adaptor proteins in contrast to FGFR-1. No phosphorylation of Ras GTPase-activating protein, p64 Syp/PTP1D tyrosine phosphatase, or association of the GRB2 adaptor protein SH2 domain with these receptors was detected. Unlike FGFR-1, FGFR-4 induced only a barely detectable phosphorylation of the cellular serine/threonine kinase Raf-1 and a weaker tyrosyl phosphorylation of mitogen-activated protein kinases than FGFR-1. Despite these differences, stimulation of both receptors resulted in increased DNA synthesis.
Insights
Fibroblast growth factor receptors (FGFRs) 1 and 4 activate distinct signaling pathways, despite similar binding and autophosphorylation. FGFR-4 uniquely phosphorylates specific proteins, leading to differential downstream effects and DNA synthesis.
Area of Science:
- Cellular signaling
- Receptor tyrosine kinases
- Molecular biology
Background:
- Fibroblast growth factor receptors (FGFRs) are crucial for cell growth and differentiation.
- FGFR-1 and FGFR-4 share similarities in ligand binding and autophosphorylation.
- Understanding differential signaling pathways is key to comprehending FGFR functions.
Purpose of the Study:
- To investigate and compare the signal transduction pathways activated by FGFR-4 and FGFR-1.
- To identify downstream signaling molecules differentially regulated by FGFR-4 and FGFR-1.
Main Methods:
- Transfection of L6 rat myoblasts and NIH3T3 mouse fibroblasts with FGFR-4 and FGFR-1.
- Analysis of tyrosine phosphorylation of signaling proteins via immunoprecipitation and Western blotting.
- Assessment of protein-protein interactions using co-precipitation assays.
Main Results:
- Both FGFR-1 and FGFR-4 exhibited similar acidic fibroblast growth factor binding and tyrosine autophosphorylation.
- FGFR-4 uniquely co-precipitated with an 85 kDa tyrosyl-phosphorylated protein doublet, not observed with FGFR-1.
- FGFR-4 showed reduced tyrosyl phosphorylation of phospholipase C-gamma, SHC proteins, Raf-1, and mitogen-activated protein kinases compared to FGFR-1.
- Neither receptor mediated phosphorylation of Ras GTPase-activating protein or Syp/PTP1D, nor GRB2 association.
Conclusions:
- FGFR-1 and FGFR-4 activate distinct intracellular signaling cascades despite initial similarities.
- FGFR-4's unique interactions and differential phosphorylation of key signaling molecules suggest specific roles in cellular processes.
- Both receptors ultimately promote DNA synthesis, indicating convergence at a later stage of signaling.