Abstract
AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer. RNA-seq studies in lung adenocarcinoma cells lacking phosphorylated IWS1, identified a exon 2-deficient U2AF2 splice variant. Here, we show that exon 2 inclusion in the U2AF2 mRNA is a cell cycle-dependent process that is regulated by LEDGF/SRSF1 splicing complexes, whose assembly is controlled by the IWS1 phosphorylation-dependent deposition of histone H3K36me3 marks in the body of target genes. The exon 2-deficient U2AF2 mRNA encodes a Serine-Arginine-Rich (RS) domain-deficient U2AF65, which is defective in CDCA5 pre-mRNA processing. This results in downregulation of the CDCA5-encoded protein Sororin, a phosphorylation target and regulator of ERK, G2/M arrest and impaired cell proliferation and tumor growth. Analysis of human lung adenocarcinomas, confirmed activation of the pathway in EGFR-mutant tumors and showed that pathway activity correlates with tumor stage, histologic grade, metastasis, relapse after treatment, and poor prognosis.
Highlights
AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer
Data presented in this report describe a signaling pathway, which starts with the AKT3-dependent phosphorylation of IWS1 and promotes cell proliferation by regulating the alternative RNA splicing of U2AF2, the RNA splicing of its target CDCA5, and the expression of the CDCA5-encoded protein Sororin
The latter is a member of a splicing complex composed of four core and three accessory polypeptides, which is recruited to RNA Pol II via its interaction with the RS domain of U2AF65
Summary
AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer. We show that exon 2 inclusion in the U2AF2 mRNA is a cell cycle-dependent process that is regulated by LEDGF/SRSF1 splicing complexes, whose assembly is controlled by the IWS1 phosphorylation-dependent deposition of histone H3K36me[3] marks in the body of target genes. Two complementary molecular mechanisms may contribute to alternative RNA splicing, the rate of transcription and chromatin modifications in the body of transcribed genes. Progression through the cell cycle depends on periodic changes of gene function, which can be achieved by multiple mechanisms, one of which is the periodic modulation of RNA splicing and spliceosomal components[14]. Exploring the links between RNA splicing and the cell cycle is likely to yield important information, with a significant impact in our understanding of human disease, especially cancer
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