J. Cell Biol., Volume 140, Number 4, February 23, 1998 737-750

SRPK2: A Differentially Expressed SR Protein-specific Kinase Involved in Mediating the Interaction and Localization of Pre-mRNA Splicing Factors in Mammalian Cells

Huan-You Wang,^* Wen Lin,^*§ Jacqueline A. Dyck,^* Joanne M. Yeakley,^* Zhou Songyang, Lewis C. Cantley,^¶ and Xiang-Dong Fu^*

^* Division of Cellular and Molecular Medicine, Department of Medicine,  Molecular Pathology Program, Department of Pathology, University of California, San Diego, La Jolla, California 92093-0651; ^§ Department of Pediatrics, Tongji Medical University and Xie He Hospital, Wuhan, Hubei 430030, P. R. China;  Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; and ^¶ Division of Signal Transduction, Beth Israel Hospital and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Abstract. Reversible phosphorylation plays an important role in pre-mRNA splicing in mammalian cells. Two kinases, SR protein-specific kinase (SRPK1) and Clk/Sty, have been shown to phosphorylate the SR family of splicing factors. We report here the cloning and characterization of SRPK2, which is highly related to SRPK1 in sequence, kinase activity, and substrate specificity. Random peptide selection for preferred phosphorylation sites revealed a stringent preference of SRPK2 for SR dipeptides, and the consensus derived may be used to predict potential phosphorylation sites in candidate arginine and serine-rich (RS) domain-containing proteins. Phosphorylation of an SR protein (ASF/SF2) by either SRPK1 or 2 enhanced its interaction with another RS domain-containing protein (U1 70K), and overexpression of either kinase induced specific redistribution of splicing factors in the nucleus. These observations likely reflect the function of the SRPK family of kinases in spliceosome assembly and in mediating the trafficking of splicing factors in mammalian cells. The biochemical and functional similarities between SRPK1 and 2, however, are in contrast to their differences in expression. SRPK1 is highly expressed in pancreas, whereas SRPK2 is highly expressed in brain, although both are coexpressed in other human tissues and in many experimental cell lines. Interestingly, SRPK2 also contains a proline-rich sequence at its NH₂ terminus, and a recent study showed that this NH₂-terminal sequence has the capacity to interact with a WW domain protein in vitro. Together, our studies suggest that different SRPK family members may be uniquely regulated and targeted, thereby contributing to splicing regulation in different tissues, during development, or in response to signaling.

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