Akt2 Regulation of Cdc2-Like Kinases (Clk/Sty), Serine/Arginine-Rich (SR) Protein Phosphorylation, and Insulin-Induced Alternative Splicing of PKCβII Messenger Ribonucleic Acid
Akt2 Regulation of Cdc2-Like Kinases (Clk/Sty), Serine/Arginine-Rich (SR) Protein Phosphorylation, and Insulin-Induced Alternative Splicing of PKCβII Messenger Ribonucleic Acid
复制标题
DOI：
10.1210/en.2008-0818
复制
发表时间：
2009-05-01
期刊：
影响因子：
4.8
通讯作者：
Cooper, Denise R.
中科院分区：
文献类型：
--
作者：
Jiang, Kun;Patel, Niketa A.;Cooper, Denise R.
富含丝氨酸/丝氨酸（SR）的蛋白质在前体mRNA的组成性和调节性剪接中起重要作用。精氨酸/丝氨酸二肽丰富（RS）结构域的SR蛋白激酶，如Cdc 2样激酶（Clk/Sty）的磷酸化调节其亚细胞定位和激活。然而，目前还不清楚这些激酶和它们的靶SR蛋白是如何被细胞外信号调节的。蛋白激酶C β II（PKC β II）前体mRNA选择性剪接的调节通过外显子包含Akt 2，胰岛素作用中的中心激酶，涉及SR蛋白的磷酸化。在这里，我们表明，Akt 2，在响应胰岛素，导致磷酸化的Clk/Sty，然后改变SR蛋白磷酸化与Akt 2。胰岛素刺激的PKC β II前体mRNA剪接被Clk/Sty和磷脂酰肌醇-3-激酶抑制剂阻断，糖尿病Akt 2缺失小鼠组织的磷酸化Clk/Sty、SR蛋白磷酸化和PKC β II表达受损。此外，我们观察到，Akt 2磷酸化的几个SR蛋白不同的Clk/Sty响应胰岛素。Akt 2催化的Clk/Sty和SR蛋白磷酸化揭示了两种激酶在剪接调节中的作用，表明Akt 2在该途径中响应胰岛素的双重功能。（内分泌学150：2087-2097，2009）
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 beta II (PKC beta II) 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 PKC beta II 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 PKC beta II 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. (Endocrinology 150: 2087-2097, 2009)