title: Phosphoproteomics identifies oncogenic Ras signaling targets and their involvement in lung adenocarcinomas.
abstract: BACKGROUND
  Ras is frequently mutated in a variety of human cancers, including lung cancer, leading to constitutive activation of MAPK signaling. Despite decades of research focused on the Ras oncogene, Ras-targeted phosphorylation events and signaling pathways have not been described on a proteome-wide scale.
  
  
  RESULTS
  By functional phosphoproteomics, we studied the molecular mechanics of oncogenic Ras signaling using a pathway-based approach. We identified Ras-regulated phosphorylation events (n = 77) using label-free comparative proteomics analysis of immortalized human bronchial epithelial cells with and without the expression of oncogenic Ras. Many were newly identified as potential targets of the Ras signaling pathway. A majority (∼60%) of the Ras-targeted events consisted of a [pSer/Thr]-Pro motif, indicating the involvement of proline-directed kinases. By integrating the phosphorylated signatures into the Pathway Interaction Database, we further inferred Ras-regulated pathways, including MAPK signaling and other novel cascades, in governing diverse functions such as gene expression, apoptosis, cell growth, and RNA processing. Comparisons of Ras-regulated phosphorylation events, pathways, and related kinases in lung cancer-derived cells supported a role of oncogenic Ras signaling in lung adenocarcinoma A549 and H322 cells, but not in large cell carcinoma H1299 cells.
  
  
  CONCLUSIONS
  This study reveals phosphorylation events, signaling networks, and molecular functions that are regulated by oncogenic Ras. The results observed in this study may aid to extend our knowledge on Ras signaling in lung cancer.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Putty-Reddy
authors.initials: PR
authors.lastname: Sudhir
authors.forename: Chia-Lang
authors.initials: CL
authors.lastname: Hsu
authors.forename: Mei-Jung
authors.initials: MJ
authors.lastname: Wang
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Wang
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Ting-Yi
authors.initials: TY
authors.lastname: Sung
authors.forename: Wen-Lian
authors.initials: WL
authors.lastname: Hsu
authors.forename: Ueng-Cheng
authors.initials: UC
authors.lastname: Yang
authors.forename: Jeou-Yuan
authors.initials: JY
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001980:Bronchi / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction
chemical_list: D010748:Phosphopeptides; D010750:Phosphoproteins