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Papers In Press, published online ahead of print January 31, 2005
Biochemistry and Molecular Biology, University of South Florida College of Medicine and J.A. Haley Veterans Hospital, Tampa, FL 33612
Corresponding Author: dcooper{at}hsc.usf.edu
Insulin regulates alternative splicing of PKCßII mRNA by phosphorylation of SRp40 via a PI3-kinase pathway (Patel et al, 2001, JBC 276:22648-54). Transient transfection of constitutively active Akt2 kinase promotes PKCßII exon inclusion. Serine/arginine rich (SR) RNA-binding proteins regulating the selection of alternatively spliced exons, are potential substrates of Akt kinase since many of them contain RXRXXS/T motifs. Here we show that Akt2 kinase phosphorylated SRp40 in vivo and in vitro. Mutation of Ser86 on SRp40 blocked in vitro phosphorylation. In control Akt2 (+/+) fibroblasts, insulin treatment increased the phosphorylation of endogenous SR proteins, but their phosphorylation state remained unaltered by insulin in fibroblasts from Akt2(-/-) mice. Levels of PKCßII protein were up-regulated by insulin in Akt2 (+/+) cells, however, only very low levels of PKCßII were detected in Akt2(-/-) cells and did not change following insulin treatment. Endogenous PKCßI and -ßII mRNA levels in Akt2(+/+) and Akt2(-/-) gastrocnemius muscle tissues were compared using quantitative real-time PCR. Results indicated a 54% decrease in the expression of PKCßII levels in Akt(-/-) while PKCßI levels remained unchanged in both samples. Further, transfection of Akt2(-/-) cells with a PKCßII splicing minigene revealed defective ßII exon inclusion. Co-transfection of the mutated SRp40 attenuated -bII exon inclusion. This study provides in vitro and in vivo evidence showing Akt2 kinase directly phosphorylated SRp40 thereby connecting the insulin, PI3-kinase/Akt pathway with phosphorylation of a site on a nuclear splicing protein promoting exon inclusion. This model is upheld in Akt2 deficient mice with insulin resistance leading to diabetes mellitus.
J. Biol. Chem, 10.1074/jbc.M411485200
Submitted on October 8, 2004
Revised on January 24, 2005
Accepted on January 31, 2005
Molecular and genetic studies imply Akt-mediated signaling promotes PKCßII alternative splicing via phosphorylation of SRp40
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