Distinct mechanisms of STAT phosphorylation via the interferon-alpha/beta receptor. Selective inhibition of STAT3 and STAT5 by piceatannol.
Interferon-alpha (IFNalpha) can activate several members of the signal transducers and activator of transcription (STAT) transcription factor family, a process that requires the tyrosine kinases Jak1 and Tyk2. Here we provide evidence that IFNalpha-mediated activation of various STAT proteins is regulated by distinct mechanisms. Piceatannol, previously reported as a Syk/ZAP70-specific kinase inhibitor, selectively inhibits the tyrosine phosphorylation of STAT3 and STAT5, but not of STAT1 and STAT2. This inhibition is paralleled by the loss of Jak1 and IFNAR1 tyrosine phosphorylation in response to IFNalpha, whereas Tyk2 and IFNAR2 tyrosine phosphorylation is unaffected. Last, the IFNalpha-induced serine phosphorylation of STAT1 and STAT3 is not inhibited by piceatannol but is sensitive to the Src kinase-specific inhibitor PP2. Thus, our results not only demonstrate that the IFNalpha/beta receptor utilizes distinct mechanisms to trigger the tyrosine phosphorylation of specific STAT proteins, but they also indicate a diverging pathway that leads to the serine phosphorylation of STAT1 and STAT3.
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Department of Biology and UCSD Cancer Center, University of California San Diego, La Jolla, California 92093-0322, USA.
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D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D053613:Janus Kinase 1; D019169:Jurkat Cells; D008565:Membrane Proteins; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D016898:Interferon-alpha; D008565:Membrane Proteins; D008894:Milk Proteins; D010975:Platelet Aggregation Inhibitors; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D013267:Stilbenes; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta; D014443:Tyrosine; D012694:Serine; C041525:3,3',4,5'-tetrahydroxystilbene; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D012260:Ribonucleases