The acidic domain and first immunoglobulin-like loop of fibroblast growth factor receptor 2 modulate downstream signaling through glycosaminoglycan modification.
Fibroblast growth factor receptors (FGFRs) are membrane-spanning tyrosine kinases that have been implicated in a variety of biological processes including mitogenesis, cell migration, development, and differentiation. We identified a unique isoform of FGFR2 expressed as a diffuse band with an unusually large molecular mass. This receptor is modified by glycosaminoglycan at a Ser residue located immediately N terminal to the acidic box, a stretch of acidic amino acids. The acidic box and the glycosaminoglycan modification site are encoded by an alternative exon of the FGFR2 gene. The acidic box appears to play an important role in glycosaminoglycan modification, and the presence of this domain is required for modification by heparan sulfate glycosaminoglycan. Moreover, the presence of the first immunoglobulin-like domain encoded by another alternative exon abrogated the modification. The high-affinity receptor with heparan sulfate modification enhanced receptor autophosphorylation, substrate phosphorylation, and ternary complex factor-independent gene expression. It also sustained mitogen-activated protein kinase activity and increased eventual DNA synthesis, a long-term response to fibroblast growth factor stimulation, at physiological ligand concentrations. We propose a novel regulation mechanism of FGFR2 signal transduction through glycosaminoglycan modification.
Sakaguchi
K
K
Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ksaka@wakayama-med.ac.jp
Lorenzi
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Bottaro
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Miki
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D017398:Alternative Splicing; D020816:Amino Acid Motifs; D004789:Enzyme Activation; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism*; D007136:Immunoglobulins / Q000378:metabolism*; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D006025:Glycosaminoglycans; D007136:Immunoglobulins; D008024:Ligands; D020033:Protein Isoforms; D016760:Proto-Oncogene Proteins c-fos; D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D020928:Mitogen-Activated Protein Kinases