SRSF2 promotes splicing and transcription of exon 11 included isoform in Ron proto-oncogene

Abstract

The product of proto-oncogene Ron is a human receptor for the macrophage-stimulating protein (MSP). Upon activation, Ron is able to induce cell dissociation, migration and matrix invasion. Exon 11 skipping of Ron pre-mRNA produces Ron△165 protein that is constitutively active even in the absence of its ligand. Here we show that knockdown of SRSF2 promotes the decrease of exon 11 inclusion, whereas overexpression of SRSF2 promotes exon 11 inclusion. We demonstrate that SRSF2 promotes exon 11 inclusion through splicing and transcription procedure. We also present evidence that reduced expression of SRSF2 induce a decrease in the splicing of both intron 10 and 11, by contrast, overexpression of SRSF2 induce an increase in the splicing of intron 10 and 11. Through mutation analysis, we show that SRSF2 functionally target and physically interact with CGAG sequence on exon 11. In addition, we reveal that weak strength of splice sites of exon 11 is not required for the function of SRSF2 on the splicing of Ron exon 11. Our results indicate that SRSF2 promotes exon 11 inclusion of Ron proto-oncogene through targeting exon 11. Our study provides a novel mechanism by which Ron is expressed.

Effects of PTCs on nonsense-mediated mRNA decay are dependent on PTC location

“…It has been demonstrated in a previous study that mutations in minigenes can affect the splicing of alternative exons (12). The results of the present study confirmed that the differential location of PTCs on alternative exons 5 and 6 may induce NMD of the majority of the spliced or partially spliced exon isoforms.…”

“…Previous studies have demonstrated that serine/arginine-rich splicing factor (SRSF) 1 and heterogeneous nuclear ribonucleoprotein A1 regulate the epithelial-to-mesenchymal transition through the regulation of exon 11 alternative splicing in RON pre-mRNA (10,11). Our previous study also identified SRSF2 as an important regulator protein for the alternative splicing of exon 11 (12). Another isoform, RONΔ160, is produced by the exclusion of exons 5 and 6 and lacks the first immunoglobulin-plexin-transcription domain in the extracellular β chain, and therefore induces cellular transformation, metastasis and protects tumor cells from apoptosis (13)(14)(15).…”

Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks

“…This is the case of NUMB, for which the reversal of the splicing change induced by RBM10 mutations in lung cancer cells can revert the proliferative phenotype (Bechara et al 2013). Events that contribute to cancer are often controlled by multiple factors, like the exon skipping event of MST1R involved in cell invasion, which is controlled by SRSF1 (Ghigna et al 2005), HNRNPA2B1 (Golan-Gerstl et al 2011), HNRNPH1, and SRSF2 (Moon et al 2014). Furthermore, some events may be affected by both mutations and expression changes in splicing factors.…”

Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks

“…This is the case of NUMB, for which the reversal of the splicing change induced by RBM10 mutations in lung cancer cells can revert the proliferative phenotype (Bechara et al 2013). Events that contribute to cancer are often controlled by multiple factors, like the exon skipping event of MST1R involved in cell invasion, which is controlled by SRSF1 (Ghigna et al 2005), HNRNPA2B1 (Golan-Gerstl et al 2011), HNRNPH1 and SRSF2 (Moon et al 2014). Furthermore, some events may be affected by both mutations and expression changes in splicing factors.…”

“…A similar example is S6K1, where expression of isoform-2 is sufficient to reverse the transformation of immortal rodent fibroblasts caused by the overexpression of SRSF1 in vitro and in vivo 9 . Events that contribute to cancer are often controlled by multiple factors, like the exon skipping event of MST1R involved in cell invasion, which is controlled by SRSF1 15 , hnRNPA2B1 12 , hnRNPH1 and SRSF2 16 . Furthermore, some events may be affected by both mutations and expression changes in splicing factors.…”