BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

RRM but not the Asp/Glu domain of hnRNP C1/C2 is required for splicing regulation of Ron exon 11 pre-mRNA

  • Moon, Heegyum (School of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Jang, Ha Na (School of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Liu, Yongchao (School of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Choi, Namjeong (School of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Oh, Jagyeong (School of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Ha, Jiyeon (School of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Kim, Hyeon Ho (Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University) ;
  • Zheng, Xuexiu (School of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Shen, Haihong (School of Life Sciences, Gwangju Institute of Science and Technology)
  • Received : 2019.03.25
  • Accepted : 2019.04.03
  • Published : 2019.11.30
Download PDF
⟨ Previous Next ⟩

Abstract

The Ron proto-oncogene is a human receptor for macrophage-stimulating protein (MSP). The exclusion of exon 11 in alternative splicing generates ${\Delta}RON$ protein that is constitutively activated. Heterogenous ribonucleaoprotein (hnRNP) $C_1/C_2$ is one of the most abundant proteins in cells. In this manuscript, we showed that both hnRNP $C_1$ and $C_2$ promoted exon 11 inclusion of Ron pre-mRNA and that hnRNP $C_1$ and hnRNP $C_2$ functioned independently but not cooperatively. Moreover, hnRNP $C_1$ stimulated exon 11 splicing through intron 10 activation but not through intron 11 splicing. Furthermore, we showed that, whereas the RRM domain was required for hnRNP $C_1$ function, the Asp/Glu domain was not. In conclusion, hnRNP $C_1/C_2$ promoted exon 11 splicing independently by stimulating intron 10 splicing through RRM but not through the Asp/Glu domain.

Keywords

References

  1. Wahl MC, Will CL and Luhrmann R (2009) The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701-718 https://doi.org/10.1016/j.cell.2009.02.009
  2. Papoff G, Cascino I, Eramo A, Starace G, Lynch DH and Ruberti G (1996) An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell death in vitro. J Immunol 156, 4622-4630
  3. Droin N, Rebe C, Bichat F, Hammann A, Bertrand R and Solary E (2001) Modulation of apoptosis by procaspase-2 short isoform: selective inhibition of chromatin condensation, apoptotic body formation and phosphatidylserine externalization. Oncogene 20, 260-269 https://doi.org/10.1038/sj.onc.1204066
  4. Kroemer G (1997) The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 3, 614-620 https://doi.org/10.1038/nm0697-614
  5. Iwama A, Okano K, Sudo T, Matsuda Y and Suda T (1994) Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells. Blood 83, 3160-3169 https://doi.org/10.1182/blood.V83.11.3160.3160
  6. Collesi C, Santoro MM, Gaudino G and Comoglio PM (1996) A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype. Mol Cell Biol 16, 5518-5526 https://doi.org/10.1128/MCB.16.10.5518
  7. Okino T, Egami H, Ohmachi H et al (1999) Presence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa. Int J Oncol 15, 709-714
  8. Ghigna C, Giordano S, Shen H et al (2005) Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell 20, 881-890 https://doi.org/10.1016/j.molcel.2005.10.026
  9. Bonomi S, di Matteo A, Buratti E et al (2013) HnRNP A1 controls a splicing regulatory circuit promoting mesenchymal-to-epithelial transition. Nucleic Acids Res 41, 8665-8679 https://doi.org/10.1093/nar/gkt579
  10. Moon H, Cho S, Loh TJ et al (2014) SRSF2 promotes splicing and transcription of exon 11 included isoform in Ron proto-oncogene. Biochim Biophys Acta 1839, 1132-1140 https://doi.org/10.1016/j.bbagrm.2014.09.003
  11. Dreyfuss G, Kim VN and Kataoka N (2002) Messenger- RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol 3, 195-205 https://doi.org/10.1038/nrm760
  12. Brunner JE, Nguyen JH, Roehl HH, Ho TV, Swiderek KM and Semler BL (2005) Functional interaction of heterogeneous nuclear ribonucleoprotein C with poliovirus RNA synthesis initiation complexes. J Virol 79, 3254-3266 https://doi.org/10.1128/JVI.79.6.3254-3266.2005
  13. McAfee JG, Shahied-Milam L, Soltaninassab SR and LeStourgeon WM (1996) A major determinant of hnRNP C protein binding to RNA is a novel bZIP-like RNA binding domain. RNA 2, 1139-1152
  14. Gorlach M, Wittekind M, Beckman RA, Mueller L and Dreyfuss G (1992) Interaction of the RNA-binding domain of the hnRNP C proteins with RNA. EMBO J 11, 3289-3295 https://doi.org/10.1002/j.1460-2075.1992.tb05407.x
  15. Zarnack K, Konig J, Tajnik M et al (2013) Direct competition between hnRNP C and U2AF65 protects the transcriptome from the exonization of Alu elements. Cell 152, 453-466 https://doi.org/10.1016/j.cell.2012.12.023
  16. Barnett SF, Friedman DL and LeStourgeon WM (1989) The C proteins of HeLa 40S nuclear ribonucleoprotein particles exist as anisotropic tetramers of $(C_{1})3$ $C_{2}$. Mol Cell Biol 9, 492-498 https://doi.org/10.1128/MCB.9.2.492
  17. Dreyfuss G, Matunis MJ, Pinol-Roma S and Burd CG (1993) hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem 62, 289-321 https://doi.org/10.1146/annurev.bi.62.070193.001445
  18. Williamson DJ, Banik-Maiti S, DeGregori J and Ruley HE (2000) hnRNP C is required for postimplantation mouse development but Is dispensable for cell viability. Mol Cell Biol 20, 4094-4105 https://doi.org/10.1128/MCB.20.11.4094-4105.2000
  19. Konig J, Zarnack K, Rot G et al (2010) iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 17, 909-915 https://doi.org/10.1038/nsmb.1838
  20. Venables JP, Koh CS, Froehlich U et al (2008) Multiple and specific mRNA processing targets for the major human hnRNP proteins. Mol Cell Biol 28, 6033-6043 https://doi.org/10.1128/MCB.00726-08
  21. Izquierdo JM (2010) Heterogeneous ribonucleoprotein C displays a repressor activity mediated by T-cell intracellular antigen-1-related/like protein to modulate Fas exon 6 splicing through a mechanism involving Hu antigen R. Nucleic Acids Res 38, 8001-8014 https://doi.org/10.1093/nar/gkq698
  22. McCloskey A, Taniguchi I, Shinmyozu K and Ohno M (2012) hnRNP C tetramer measures RNA length to classify RNA polymerase II transcripts for export. Science 335, 1643-1646 https://doi.org/10.1126/science.1218469
  23. Moon H, Cho S, Loh TJ et al (2017) SRSF2 directly inhibits intron splicing to suppresses cassette exon inclusion. BMB Rep 50, 423-428 https://doi.org/10.5483/BMBRep.2017.50.8.103