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¹ Horizontal Medical Research Organization (HMRO), Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
² Department of Functional Genomics, Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
³ Medical Top Track (MTT) Program, Medical Research Institute, Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
⁴ Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
⁵ Division of Regeneration and Advanced Medical Science, Graduate School of Medicine, Gifu University, Gifu 501-1193, Japan
⁶ Molecular Probe & Drug Design Laboratory, Molecular Imaging Research Program, RIKEN, Kobe 650-0047, Japan
⁷ Laboratory of Gene Expression, Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
⁸ Cell Biology Group, Kansai Advanced Research Center, National Institute of Information and Communications Technology, Kobe 651-2492, Japan
⁹ Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan

SR proteins are non-snRNP splicing factors harbouring a domain rich in Arg-Ser repeats, which are extensively phosphorylated by several kinases. We performed a comparative study of different SR kinases, including SRPK, Clk, PRP4 and DYRK, and found that only Clks efficiently altered 5' splice site selection of Adenovirus E1A. The phosphorylation state of SR proteins was examined using a phospho-SR specific antibody mAb1H4 and a 75 kDa protein was most evidently hyperphosphorylated by Clks. Administration of TG003, a specific inhibitor for the Clk family members, specifically and rapidly induced dephosphorylation of 75 kDa SR protein. Imaging with mRFP-SRp75 in living cells revealed that its nuclear distribution was rapidly altered upon inhibition of the Clk activity by TG003. Co-transfection experiments demonstrated that HA-tagged SRp75 was hyperphosphorylated by Clk family members, but not by other SR kinases. These results indicate that Clks specifically hyperphosphorylate SRp75. Furthermore, SRp75 over-expression promoted the selection of 12S 5' splice site in E1A pre-mRNA, which is stimulated by co-expression of Clks. These results suggest that the specific combination of SR protein and SR kinase plays a distinct role in alternative splicing through dynamic balance of phosphorylation.

^aPresent address: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093, USA.

^* Correspondence: E-mail: hkimura{at}fbs.osaka-u.ac.jp

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