Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes.
We sought to explore the relationship between receptor tyrosine kinase (RTK) activated signaling pathways and the transcriptional induction of immediate early genes (IEGs). Using global expression monitoring, we identified 66 fibroblast IEGs induced by platelet-derived growth factor beta receptor (PDGFRbeta) signaling. Mutant receptors lacking binding sites for activation of the PLCgamma, PI3K, SHP2, and RasGAP pathways still retain partial ability to induce 64 of these IEGs. Removal of the Grb2-binding site further broadly reduces induction. These results suggest that the diverse pathways exert broadly overlapping effects on IEG induction. Interestingly, a mutant receptor that restores the RasGAP-binding site promotes induction of an independent group of genes, normally induced by interferons. Finally, we compare the PDGFRbeta and fibroblast growth factor receptor 1; each induces essentially identical IEGs in fibroblasts.
Fambrough
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Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
McClure
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Kazlauskas
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Lander
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ES
D016475:3T3 Cells; D000818:Animals; D002461:Cell Line, Transformed; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D005807:Genes, Overlapping; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D016296:Mutagenesis; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D017468:Receptors, Fibroblast Growth Factor; D014443:Tyrosine; D010649:Phenylalanine; D007371:Interferon-gamma; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor