Distinct mechanisms of STAT phosphorylation via the interferon-α/β receptor -: Selective inhibition of STAT3 and STAT5 by piceatannol

Interferon-alpha (IFN alpha) 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 IFN alpha-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 STATE. This inhibition is paralleled by the loss of Jak1 and IFNAR1 tyrosine phosphorylation in response to IFN alpha, whereas Tyk2 and IFNAR2 tyrosine phosphorylation is unaffected. Last, the IFN alpha-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 IFN alpha/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.