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J. Biol. Chem., Vol. 280, Issue 15, 15340-15347, April 15, 2005

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Protein Kinase CK1 Regulates mRNA Binding by Heterogeneous Nuclear Ribonucleoprotein C in Response to Physiologic Levels of Hydrogen Peroxide^*

Taj Kattapuram, Suping Yang, Jenny L. Maki, and James R. Stone

From the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

At low concentrations, hydrogen peroxide (H₂O₂) is a positive endogenous regulator of mammalian cell proliferation and survival; however, the signal transduction pathways involved in these processes are poorly understood. In primary human endothelial cells, low concentrations of H₂O₂ stimulated the rapid phosphorylation of the acidic C-terminal domain (ACD) of heterogeneous nuclear ribonucleoprotein C (hnRNP-C), a nuclear restricted pre-mRNA-binding protein, at Ser²⁴⁰ and at Ser²²⁵–Ser²²⁸. A kinase activity was identified in mouse liver that phosphorylates the ACD of hnRNP-C at Ser²⁴⁰ and at two sites at Ser²²⁵–Ser²²⁸. The kinase was purified and identified by tandem mass spectrometry as protein kinase CK1 (formerly casein kinase 1). Protein kinase CK1 immunoprecipitated from primary human endothelial cell nuclei also phosphorylated the ACD of hnRNP-C at these positions. Pretreatment of endothelial cells with the protein kinase CK1-specific inhibitor IC261 prevented the H₂O₂-stimulated phosphorylation of hnRNP-C. Utilizing phosphoserine-mimicking Ser-to-Glu point mutations, the effects of phosphorylation on hnRNP-C function were investigated by quantitative equilibrium fluorescence RNA binding analyses. Wild-type hnRNP-C1 and hnRNP-C1 modified at the basal sites of phosphorylation (S247E and S286E) both avidly bound RNA with similar binding constants. In contrast, hnRNP-C1 that was also modified at the CK1 phosphorylation sites exhibited a 14–500-fold decrease in binding affinity, demonstrating that CK1-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C.

Received for publication, January 6, 2005 , and in revised form, January 31, 2005.

^* This work was supported by National Institutes of Health Grant HL074324. 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.

Present address: Dept. of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003.

To whom correspondence should be addressed: Dept. of Pathology, Massachusetts General Hospital, Warren 501B, 55 Fruit St., Boston, MA 02114. Tel.: 617-726-8303; Fax: 617-726-2365; E-mail: jrstone{at}partners.org.

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