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Molecular and Cellular Biology, June 2003, p. 4139-4149, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4139-4149.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation and Substrate Specificity of the SR Protein Kinase Clk/Sty

Jayendra Prasad* and James L. Manley

Department of Biological Sciences, Columbia University, New York, New York 10027

Received 3 February 2003/ Returned for modification 5 March 2003/ Accepted 25 March 2003

SR proteins constitute a family of splicing factors that play key roles in both constitutive and regulated splicing in metazoan organisms. The proteins are extensively phosphorylated, and kinases capable of phosphorylating them have been identified. However, little is known about how these kinases function, for example, whether they target specific SR proteins or whether the kinases themselves are regulated. Here we describe properties of one such kinase, Clk/Sty, the founding member of the Clk/Sty family of dual-specificity kinases. Clk/Sty is autophosphorylated on both Ser/Thr and Thr residues, and using both direct kinase assays and SR protein-dependent splicing assays, we have analyzed the effects of each type of modification. We find not only that the pattern of phosphorylation on a specific SR protein substrate, ASF/SF2, is modulated by autophosphorylation but also that the ability of Clk/Sty to recognize different SR proteins is influenced by the extent and nature of autophosphorylation. Strikingly, phosphorylation of ASF/SF2 is sensitive to changes in Tyr, but not Ser/Thr, autophosphorylation while that of SC35 displays the opposite pattern. In contrast, phosphorylation of a third SR protein, SRp40, is unaffected by autophosphorylation. We also present biochemical data indicating that as expected for a factor directly involved in splicing control (but in contrast to recent reports), Clk/Sty is found in the nucleus of several different cell types.

* Corresponding author. Mailing address: Lerner Research Institute, Department of Molecular Biology NC-20, Cleveland Clinic Foundation, Cleveland, OH 44195. Phone: (216) 445-2693. Fax: (216) 444-0512. E-mail: jayendra10025{at}yahoo.com.

Molecular and Cellular Biology, June 2003, p. 4139-4149, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4139-4149.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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