Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation.
Interferons induce transcriptional activation through tyrosine phosphorylation of the latent, cytoplasmic transcription factor interferon-stimulated gene factor-3 (ISGF-3). Growth factors and cytokines were found to use a similar pathway: The 91-kilodalton subunit of ISGF-3 was activated and tyrosine phosphorylated in response to epidermal growth factor (EGF), platelet-derived growth factor, and colony stimulating factor-1. The tyrosine phosphorylated factor acquired DNA binding activity and accumulated in nuclei. Activation required the major sites for autophosphorylation on the EGF receptor that bind Src homology region 2 domain-containing proteins implicated in Ras activation. However, activation of this factor was independent of the normal functioning of Ras.
Department of Pharmacology, New York University School of Medicine, New York, 10016.
O
O
Silvennoinen
C
C
Schindler
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J
Schlessinger
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DE
Levy
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D011905:Genes, ras; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D004268:DNA-Binding Proteins; D006133:Growth Substances; C494227:IRF9 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; C494228:Isgf3g protein, mouse; D010982:Platelet-Derived Growth Factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014443:Tyrosine; D004815:Epidermal Growth Factor; D016173:Macrophage Colony-Stimulating Factor; D066246:ErbB Receptors