title: Novel splicing variants of recepteur d'origine nantais (RON) tyrosine kinase involving exons 15-19 in lung cancer.
abstract: BACKGROUND
  Altered expressions of receptor tyrosine kinases drive the growth and metastasis of several cancers. RON is a single pass transmembrane receptor tyrosine kinase (RTK) shown to be aberrantly expressed in various cancer types. However, target validation and successful therapeutic targeting of RON in cancers is hampered by the co-existence of unknown number/types of isoforms, which are structurally similar but functionally diverse.
  
  
  OBJECTIVE
  The objective of this study was to identify differential splicing in the C-terminal region of RON transcripts to better understand RON signaling in cancers. mRNA transcript sequence between exons 14 and 20 of RON was PCR amplified and sequenced using cDNA from 10 SCLC and 13 NSCLC cell lines. Specific exon deletions were identified by aligning sequencing chromatograms with reference RON cDNA sequence.
  
  
  RESULTS
  We identified the presence of four unique transcript sequence variants of RON formed through skipping of exons 15-19, 16-19, 16-17 and 16. The transcript variants, except the one lacking exons 15-19, were found in more than one cell line. Several cell lines contained two to four of these uniquely spliced transcript variants. dbEST (Expressed Sequence Tags database) or other DNA sequence databases did not contain RON cDNA sequences corresponding to any of the above exon deletions indicating that all these transcript sequence alterations are novel.
  
  
  CONCLUSIONS
  Results of our study indicate common occurrence of different types of alternatively spliced transcripts of RON in lung cancer with potential to be translated into proteins lacking active kinase domain. Our findings suggest that tumors produce several dominant negative isoforms which probably inhibit ligand dependent RON signaling, and hence, raise important questions regarding the appropriateness of blocking wild type RON signaling for therapy. Further, presence of transcript variants and their isoform products may interfere with quantitative and functional analysis during target validation.
authors.affiliation: Biomarkers Research Program, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia; Prince Mutaib Chair for Biomarkers of Osteoporosis, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia. Electronic address: ksounder@gmail.com.
authors.forename: Soundararajan
authors.initials: S
authors.lastname: Krishnaswamy
authors.affiliation: Biomarkers Research Program, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia; Prince Mutaib Chair for Biomarkers of Osteoporosis, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia. Electronic address: makhaderonline@gmail.com.
authors.forename: Abdul Khader
authors.initials: AK
authors.lastname: Mohammed
authors.affiliation: Biomarkers Research Program, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia; Prince Mutaib Chair for Biomarkers of Osteoporosis, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia. Electronic address: osamaemam@gmail.com.
authors.forename: Osama E
authors.initials: OE
authors.lastname: Amer
authors.affiliation: Division of Metabolic and Vascular Research, University of Warwick, Coventry CV2 2DX, UK. Electronic address: g.tripathi@warwick.ac.uk.
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Tripathi
authors.affiliation: Biomarkers Research Program, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia; Prince Mutaib Chair for Biomarkers of Osteoporosis, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia. Electronic address: msa85@yahoo.co.uk.
authors.forename: Majed S
authors.initials: MS
authors.lastname: Alokail
authors.affiliation: Biomarkers Research Program, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia; Prince Mutaib Chair for Biomarkers of Osteoporosis, Riyadh Biochemistry Department, College of Science, King Saud University, 11451 Riyadh, Saudi Arabia. Electronic address: aldaghri2011@gmail.com.
authors.forename: Nasser M
authors.initials: NM
authors.lastname: Al-Daghri
mesh_terms: D017398:Alternative Splicing; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D005091:Exons; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017423:Sequence Analysis, RNA; D017384:Sequence Deletion; D055752:Small Cell Lung Carcinoma / Q000201:enzymology / Q000235:genetics
chemical_list: C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: Alternative splicing; MST1R; RON; RON isoforms; Receptor tyrosine kinase