Activation of Protein Kinase Cη by Type I Interferons

doi:10.1074/jbc.M807254200

Activation of Protein Kinase Cη by Type I Interferons*

^‡Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Northwestern University Medical School and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60611, ^§Division of Cell and Molecular Biology, University Health Network and Department of Immunology, Toronto Research Institute, University of Toronto, Toronto, Ontario M5G 2M1, Canada, and ^¶Section of Hematology/Oncology, Department of Medicine, Cancer Research Center, University of Chicago, Chicago, Illinois 60637

1 To whom correspondence should be addressed: Robert H. Lurie Comprehensive Cancer Center, 303 East Superior St., Lurie 3-107, Chicago, IL 60611. Tel.: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias{at}northwestern.edu.

Abstract

Type I interferons (IFNs) are cytokines with diverse biological properties, including antiviral, growth inhibitory, and immunomodulatory effects. Although several signaling pathways are activated during engagement of the type I IFN receptor and participate in the induction of IFN responses, the mechanisms of generation of specific signals for distinct biological effects remain to be elucidated. We provide evidence that a novel member of the protein kinase C (PKC) family of proteins is rapidly phosphorylated and activated during engagement of the type I IFN receptor. In contrast to other members of the PKC family that are also regulated by IFN receptors, PKCη does not regulate IFN-inducible transcription of interferon-stimulated genes or generation of antiviral responses. However, its function promotes cell cycle arrest and is essential for the generation of the suppressive effects of IFNα on normal and leukemic human myeloid (colony-forming unit-granulocyte macrophage) bone marrow progenitors. Altogether, our studies establish PKCη as a unique element in IFN signaling that plays a key and essential role in the generation of the regulatory effects of type I IFNs on normal and leukemic hematopoiesis.

Footnotes

↵2 The abbreviations used are: IFN, interferon; PKC, protein kinase C; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; siRNA, short interfering RNA; RT, reverse transcription; ISRE, interferon-stimulated response element; CFU-GM, colony-forming unit-granulocyte macrophage; BFU-E, burst-forming unit-erythroid; CML, chronic myelogenous leukemia; EMCV, encephalomyocarditis virus.
↵* This work was supported, in whole or in part, by National Institutes of Health Grants CA77816, CA100579, and CA121192 (to L. C. P.) and CA098550 (to A. W.). This work was also supported by a grant from the Department of Veterans Affairs (to L. C. P.), Predoctoral National Research Service Award F30ES015668 (to A. J. R.), and a Malkin Scholars Award (to A. J. R.).
- Received September 18, 2008.
- Revision received February 5, 2009.
The American Society for Biochemistry and Molecular Biology, Inc.