title: Akt2 regulation of Cdc2-like kinases (Clk/Sty), serine/arginine-rich (SR) protein phosphorylation, and insulin-induced alternative splicing of PKCbetaII messenger ribonucleic acid.
abstract: 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 betaII (PKCbetaII) 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 PKCbetaII 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 PKCbetaII 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.
authors.affiliation: Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Jiang
authors.forename: Niketa A
authors.initials: NA
authors.lastname: Patel
authors.forename: James E
authors.initials: JE
authors.lastname: Watson
authors.forename: Hercules
authors.initials: H
authors.lastname: Apostolatos
authors.forename: Eden
authors.initials: E
authors.lastname: Kleiman
authors.forename: Olivia
authors.initials: O
authors.lastname: Hanson
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Denise R
authors.initials: DR
authors.lastname: Cooper
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D064546:Protein Kinase C beta; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D000068103:Serine-Arginine Splicing Factors
chemical_list: D007328:Insulin; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D064546:Protein Kinase C beta