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Molecular and Cellular Biology, July 2002, p. 4535-4543, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4535-4543.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

c-Src-Mediated Phosphorylation of hnRNP K Drives Translational Activation of Specifically Silenced mRNAs

Antje Ostareck-Lederer,1* Dirk H. Ostareck,1 Christophe Cans,1 Gitte Neubauer,1 Karol Bomsztyk,2 Giulio Superti-Furga,1 and Matthias W. Hentze1*

European Molecular Biology Laboratory, Heidelberg, Germany, and,1 Department of Medicine, University of Washington, Seattle, Washington2

hnRNPK and hnRNP E1/E2 mediate translational silencing of cellular and viral mRNAs in a differentiation-dependent way by binding to specific regulatory sequences. The translation of 15-lipoxygenase (LOX) mRNA in erythroid precursor cells and of the L2 mRNA of human papilloma virus type 16 (HPV-16) in squamous epithelial cells is silenced when either of these cells is immature and is activated in maturing cells by unknown mechanisms. Here we address the question of how the silenced mRNA can be translationally activated. We show that hnRNP K and the c-Src kinase specifically interact with each other, leading to c-Src activation and tyrosine phosphorylation of hnRNP K in vivo and in vitro. c-Src-mediated phosphorylation reversibly inhibits the binding of hnRNP K to the differentiation control element (DICE) of the LOX mRNA 3' untranslated region in vitro and specifically derepresses the translation of DICE-bearing mRNAs in vivo. Our results establish a novel role of c-Src kinase in translational gene regulation and reveal a mechanism by which silenced mRNAs can be translationally activated.

* Corresponding author. Mailing address: European Molecular Biology Laboratory, Meyerhofstr. 1, D-69117 Heidelberg, Germany. Phone: 49 6221 387 501. Fax: 49 6221 387 518. E-mail for Antje Ostareck-Lederer: aostareck{at}anadyspharma.de.

* Corresponding author. Mailing address: European Molecular Biology Laboratory, Meyerhofstr. 1, D-69117 Heidelberg, Germany. Phone: 49 6221 387 501. Fax: 49 6221 387 518. E-mail for Matthias W. Hentze: hentze{at}embl-heidelberg.de.

Molecular and Cellular Biology, July 2002, p. 4535-4543, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4535-4543.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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