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Activation of Pre-mRNA Splicing by Human RNPS1 Is Regulated by CK2 Phosphorylation

Janeen H. Trembley,^1, Sawako Tatsumi,^2,, Eiji Sakashita,^2,3 Pascal Loyer,^1,4 Clive A. Slaughter,⁵ Hitoshi Suzuki,² Hitoshi Endo,³ Vincent J. Kidd,¹ and Akila Mayeda^2*

Department of Genetics and Tumor Cell Biology,¹ Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee,⁵ Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida,² Department of Biochemistry, Jichi Medical School, Kawachi-gun, Tochigi, Japan,³ INSERM U522, Hôpital Pontchaillou, Rennes, France⁴

Received 25 February 2004/ Returned for modification 6 April 2004/ Accepted 29 October 2004

Human RNPS1 was originally characterized as a pre-mRNA splicing activator in vitro and was shown to regulate alternative splicing in vivo. RNPS1 was also identified as a protein component of the splicing-dependent mRNP complex, or exon-exon junction complex (EJC), and a role for RNPS1 in postsplicing processes has been proposed. Here we demonstrate that RNPS1 incorporates into active spliceosomes, enhances the formation of the ATP-dependent A complex, and promotes the generation of both intermediate and final spliced products. RNPS1 is phosphorylated in vivo and interacts with the CK2 (casein kinase II) protein kinase. Serine 53 (Ser-53) of RNPS1 was identified as the major phosphorylation site for CK2 in vitro, and the same site is also phosphorylated in vivo. The phosphorylation status of Ser-53 significantly affects splicing activation in vitro, but it does not perturb the nuclear localization of RNPS1. In vivo experiments indicated that the phosphorylation of RNPS1 at Ser-53 influences the efficiencies of both splicing and translation. We propose that RNPS1 is a splicing regulator whose activator function is controlled in part by CK2 phosphorylation.

We dedicate this article to the memory of our colleague and mentor, Vincent J. Kidd, who suddenly passed away in May 2004. Through his research on CDK11 signaling and cell death pathways, he made significant contributions to the fields of cell cycle, transcription-splicing, apoptosis, and neuroblastoma.

J.H.T. and S.T. contributed equally to this work.

Present address: Department of Bone and Joint Diseases, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522, Japan.

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