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Molecular and Cellular Biology, October 1999, p. 6991-7000, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Protein Kinase Clk/Sty Directly Modulates SR Protein Activity: Both Hyper- and Hypophosphorylation Inhibit Splicing

Jayendra Prasad,1 Karen Colwill,2,dagger Tony Pawson,2 and James L. Manley1,*

Department of Biological Sciences, Columbia University, New York, New York 10027,1 and Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada M5G 1X52

Received 24 May 1999/Returned for modification 8 July 1999/Accepted 21 July 1999

The splicing of mammalian mRNA precursors requires both protein phosphorylation and dephosphorylation, likely involving modification of members of the SR protein family of splicing factors. Several kinases have been identified that can phosphorylate SR proteins in vitro, and transfection assays have provided evidence that at least one of these, Clk/Sty, can modulate splicing in vivo. But evidence that a specific kinase can directly affect the splicing activity of SR proteins has been lacking. Here, by using purified recombinant Clk/Sty, a catalytically inactive mutant, and individual SR proteins, we show that Clk/Sty directly affects the activity of SR proteins, but not other essential splicing factors, in reconstituted splicing assays. We also provide evidence that both hyper- and hypophosphorylation inhibit SR protein splicing activity, repressing constitutive splicing and switching alternative splice site selection. These findings indicate that Clk/Sty directly and specifically influences the activity of SR protein splicing factors and, importantly, show that both under- and overphosphorylation of SR proteins can modulate splicing.

* Corresponding author. Mailing address: Department of Biological Sciences, Columbia University, 1212 Amsterdam Ave., New York, NY 10027. Phone: (212) 854-4647. Fax: (212) 865-8246. E-mail: jlm2{at}columbia.edu.

dagger Present address: Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

Molecular and Cellular Biology, October 1999, p. 6991-7000, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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