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© The Rockefeller University Press, 0021-9525/1998//737 $5.00
The Journal of Cell Biology, Volume 140, Number 4, , 1998 737-750

Article

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*,{ddagger}, 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, {ddagger} 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.

We thank Susan Taylor of University of California at San Diego (UCSD; La Jolla, CA) (UCSD) for many useful discussions on kinase structure and function, and Marius Sudol (Mount Sinai School of Medicine, New York) for many stimulating discussions. We are grateful to B. Blencowe and P. Sharp (Massachusetts Institute of Technology, Cambridge, MA) for B1C8 antibody, L. De Jong (University of Amsterdam) for the 5E10 anti-PML antibody, D. Black (University of California, Los Angeles, Los Angeles, CA) for Weri-1 and Lan5 cell lines, C. Glass (UCSD) for U937 and THP1 cell lines, M. Kamps (UCSD) for HBL100 and HT1080 cell lines, and J. Wang (UCSD) for Bosc23 and Soas2 cell lines. The authors thank members of the Fu lab for cooperation and suggestions during the course of this study, especially S. Chandler for help in SRPK2 expression and purification, and L. Feng for help in immunohistochemistry.

J.A. Dyck and J.M. Yeakley are supported by fellowships from Damon Runyon-Walter Winchell Foundation and National Institutes of Health (NIH), respectively. X-D. Fu is a Leukemia Society of American Scholar. This work was supported by a grant from NIH (GM52872) to X-D. Fu.

Address all correspondence to Xiang-Dong Fu, Division of Cellular and Molecular Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0651. Tel.: (619) 534-4937. Fax: (619) 534-8549. E-mail: xdfu{at}ucsd.edu

1. Abbreviations used in this paper: GFP, green fluorescent protein; GST, glutathione-S-transferase; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; RS, arginine and serine-rich; RSR, arginine-serine-arginine; SH3, src homology 3; snRNP, small nuclear ribonucleoprotein particle; SRPK, SR protein-specific kinase; tTA, tetracycline-controlled transactivator.


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