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J. Biol. Chem., Vol. 278, Issue 30, 27772-27780, July 25, 2003

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Activation of the p70 S6 Kinase and Phosphorylation of the 4E-BP1 Repressor of mRNA Translation by Type I Interferons^*

From the ^aRobert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Lakeside Veterans Administration Medical Center, Chicago, Illinois 60611, the ^cSection of Hematology-Oncology, University of Chicago, Chicago, Illinois 60637, the ^gDivision of Cell & Molecular Biology, Toronto Research Institute, University Health, Network and Department of Immunology, University of Toronto, Toronto, Ontario M5S 3E2, Canada, the ^dDivision of Signal Transduction, Beth Israel Medical Center, Harvard Medical School, Boston, Massachusetts 02115, the ^eInstitut fuer Biochemie, Freie Universitaet Berlin, Berlin 14195, Germany, the ^hDepartment of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada, and the ⁱDepartment of Molecular Genetics, University of Illinois, Chicago, Illinois 60607

The Type I IFN receptor-generated signals required for initiation of mRNA translation and, ultimately, induction of protein products that mediate IFN responses, remain unknown. We have previously shown that IFN and IFN induce phosphorylation of insulin receptor substrate proteins and downstream engagement of the phosphatidylinositol (PI) 3'-kinase pathway. In the present study we provide evidence for the existence of a Type I IFN-dependent signaling cascade activated downstream of PI 3'-kinase, involving p70 S6 kinase. Our data demonstrate that p70 S6K is rapidly phosphorylated on threonine 421 and serine 424 and is activated during treatment of cells with IFN or IFN. Such activation of p70 S6K is blocked by pharmacological inhibitors of the PI 3'-kinase or the FKBP 12-rapamycin-associated protein/mammalian target of rapamycin (FRAP/mTOR). Consistent with this, the Type I IFN-dependent phosphorylation/activation of p70 S6K is defective in embryonic fibroblasts from mice with targeted disruption of the p85 and p85 subunits of the PI 3'-kinase (p85–/––/–). Treatment of sensitive cell lines with IFN or IFN also results in phosphorylation/inactivation of the 4E-BP-1 repressor of mRNA translation. Such 4E-BP1 phosphorylation is also PI3'-kinase-dependent and rapamycin-sensitive, indicating that the Type I IFN-inducible activation of PI3'-kinase and FRAP/mTOR results in dissociation of 4E-BP1 from the eukaryotic initiation factor-4E (eIF4E) complex. Altogether, our data establish that the Type I IFN receptor-activated PI 3'-kinase pathway mediates activation of the p70 S6 kinase and inactivation of 4E-BP1, to regulate mRNA translation and induction of Type I IFN responses.

Received for publication, February 7, 2003 , and in revised form, May 13, 2003.

^* This work was supported in part 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 for Health Research Grant MOP-15094 (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.

^b Both authors contributed equally to this work and are first co-authors.

^f Recipient of a fellowship from Boehringer Ingelheim Funds.

^j 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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