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by IFN-
1
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* Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, Chicago, IL 60611;
Lakeside Veterans Administration Medical, Center, Chicago, IL 60611;
Section of Hematology-Oncology and
Department of Pharmacology, University of Illinois, Chicago, IL 60607;
¶
Division of Cell and Molecular Biology, Toronto General Research Institute, University Health, Network, Toronto, Canada; and
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Department of Immunology, University of Toronto, Toronto, Canada
Engagement of the type II IFN (IFN-
) receptor results in activation of the Janus kinase-Stat pathway and induction of gene transcription via IFN--activated site (GAS) elements in the promoters of IFN--inducible genes. An important event in IFN--dependent gene transcription is phosphorylation of Stat1 on Ser727, which is regulated by a kinase activated downstream of the phosphatidylinositol 3'-kinase. Here we provide evidence that a member of the protein kinase C (PKC) family of proteins is activated downstream of the phosphatidylinositol 3'-kinase and is engaged in IFN- signaling. Our data demonstrate that PKC
is rapidly phosphorylated during engagement of the type II IFNR and its kinase domain is induced. Subsequently, the activated PKC associates with a member of the Stat family of proteins, Stat1, which acts as a substrate for its kinase activity and undergoes phosphorylation on Ser727. Inhibition of PKC activity diminishes phosphorylation of Stat1 on Ser727 and IFN--dependent transcriptional regulation via IFN--activated site elements, without affecting the phosphorylation of the protein on Tyr701. Thus, PKC is activated during engagement of the IFN- receptor and plays an important role in IFN- signaling by mediating serine phosphorylation of Stat1 and facilitating transcription of IFN--stimulated genes.
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