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Akt2 Regulation of Cdc2-Like Kinases (Clk/Sty), Serine/Arginine-Rich (SR) Protein Phosphorylation, and Insulin-Induced Alternative Splicing of PKCβII Messenger Ribonucleic Acid

Department of Molecular Medicine (K.J., N.A.P., H.A., E.K., D.R.C.), University of South Florida College of Medicine, and Research Service (N.A.P., J.E.W., D.R.C.), J. A. Haley Veterans Hospital, Tampa, Florida 33612; Department of Chemistry (O.H.), University of Central Oklahoma, Edmond, Oklahoma 73034; and Laboratory of Gene Expression (M.H.), School of Biomedical Science, Department of Functional Genomics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-Ku Tokyo 113-8510, Japan

Address all correspondence and requests for reprints to: Denise R. Cooper, Ph.D., Research Service 151, J. A. Haley Veterans Hospital, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612. E-mail: dcooper{at}hsc.usf.edu.

Serine/arginine-rich (SR) proteins play essential roles in the constitutive and regulated splicing of precursor mRNAs. Phosphorylation of the arginine/serine dipeptide-rich (RS) domain by SR protein kinases such as Cdc2-like kinases (Clk/Sty) modulates their subcellular localization and activation. However, it remains unclear how these kinases and their target SR proteins are regulated by extracellular signals. Regulation of protein kinase C βII (PKCβII) pre-mRNA alternative splicing via exon inclusion by Akt2, a central kinase in insulin action, involves phosphorylation of SR proteins. Here we showed that Akt2, in response to insulin, resulted in phosphorylation of Clk/Sty, which then altered SR protein phosphorylation in concert with Akt2. Insulin-stimulated PKCβII pre-mRNA splicing was blocked by Clk/Sty and phosphatidylinositol-3-kinase inhibitors, and diabetic Akt2-null mouse tissues had impaired phospho-Clk/Sty, SR protein phosphorylation, and PKCβII expression. Furthermore, we observed that Akt2 phosphorylated several SR proteins distinct from Clk/Sty in response to insulin. Akt2-catalyzed phosphorylation of Clk/Sty and SR proteins revealed a role for both kinases in splicing regulation indicating dual functions for Akt2 in response to insulin in this pathway.