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J. Biol. Chem., Vol. 280, Issue 11, 10001-10010, March 18, 2005

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Activation of Mitogen-activated Protein Kinase Kinase (MKK) 3 and MKK6 by Type I Interferons^*

Yongzhong Li, Sandeep Batra, Antonella Sassano, Beata Majchrzak, David E. Levy¶, Matthias Gaestel||, Eleanor N. Fish, Roger J. Davis**, and Leonidas C. Platanias

From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Lakeside Veterans Affairs Medical Center, Chicago, Illinois 60611, the Division of Cell & Molecular Biology, Toronto Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, Ontario M5G2M1, Canada, the ^¶Department of Pathology, New York University School of Medicine, New York, New York 10016, the ^||Institute of Biochemistry, Hannover Medical School, Hannover 30625, Germany, and the ^**Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts, Worcester, Massachusetts 01605

There is accumulating evidence that the p38 MAP kinase pathway plays important roles in Type I interferon (IFN) signaling, but the mechanisms regulating p38 activation during engagement of the Type I IFN receptor remain to be defined. We sought to identify the events that lead to activation of the p38 MAP kinase in response to Type I IFNs. Our data demonstrate that treatment of sensitive cell lines with IFN results in activation of both MAP kinase kinase 3 (MKK3) and MAP kinase kinase 6 (MKK6). Such IFN-inducible activation of MKK3 and MKK6 is essential for downstream phosphorylation and activation of the p38 MAP kinase, as shown by studies using mouse embryonic fibroblasts (MEFs) with targeted disruption of the Mkk3 and Mkk6 genes (MKK3–/– MKK6–/–). Similarly, IFN-dependent activation of the downstream effectors of p38, MAPKAPK-2 and MAPKAPK-3, is not detectable in cells lacking Mkk3 and Mkk6, demonstrating that the function of these MAP kinase kinases is required for full activation of the p38 pathway. To define the functional relevance of MKK3/6 engagement in Type I IFN signaling, IFN-inducible gene transcription was evaluated in the MKK3/MKK6 double knock-out cells. IFN- and IFN-dependent transcription via either interferon-stimulated response element or IFN activated site elements was defective in MKK3 –/–/MKK6 –/– MEFs in luciferase reporter assays. In addition, IFN-dependent induction of two genes known to be of importance in the generation of IFN responses, Isg15 and Irf-9, was diminished in the absence of Mkk3 and Mkk6. The effects of Mkk3 and Mkk6 on IFN-dependent transcription were unrelated to any effects on the phosphorylation and activation of STAT proteins, indicating the presence of a STAT-independent mechanism. Altogether, our findings demonstrate that MKK3 and MKK6 are rapidly activated during engagement of the Type I IFN receptor and play important roles in Type I IFN signaling and the generation of IFN responses.

Received for publication, September 23, 2004 , and in revised form, January 4, 2005.

^* This work was supported by National Institutes of Health Grants CA77816 and CA94079 (to L. C. P.), a Merit review grant from the Department of Veterans Affairs (to L. C. P.), and Canadian Institutes of Health Research Grant MOP15094(to E. N. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, 710 North Fairbanks St., Olson 8250, Chicago, IL 60611. Tel.: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias{at}northwestern.edu.

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