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J. Biol. Chem. 275 (17): 12661-12666

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

J Biol Chem, Vol. 275, Issue 17, 12661-12666, April 28, 2000

Distinct Mechanisms of STAT Phosphorylation via the Interferon-alpha /beta Receptor

Leon Su and Michael DavidDagger

From the Department of Biology and UCSD Cancer Center, University of California San Diego, La Jolla, California 92093-0322

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.

* This work was supported by National Cancer Institute Grant 1R01 CA80105 (to M. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of the Sidney Kimmel Scholar Award. To whom correspondence should be addressed: Dept. of Biology, University of California, San Diego, Bonner Hall 3138, 9500 Gilman Dr., La Jolla, CA 92093-0322. Tel.: 619-822-1108; Fax: 619-822-1106; E-mail:

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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