The Clk2 and Clk3 dual-specificity protein kinases regulate the intranuclear distribution of SR proteins and influence pre-mRNA splicing

The three members of the CLK family of kinases (Clk1, 2, and 3) have been shown to undergo conserved alternative splicing to generate catalytically active (CLK) and inactive (ClkT) isoforms. The prototype, murine Clk1 (mClk1), is a nuclear dual-specificity kinase that can interact with, and cause the nuclear redistribution of, SR proteins. In this study, we demonstrate that the human Clk2 and Clk3 (hClk2 and 3) are also found within the nucleus and display dual-specificity kinase activity. The truncated isoforms, hClk2(T) and hClk3(T), colocalize with SR proteins in nuclear speckles. We also show catalytically active hClk2 and hClk3 cause the redistribution of SR proteins and can regulate the alternative splicing of a model precursor mRNA substrate in vivo.