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Phosphoproteomics Identifies Oncogenic Ras Signaling Targets and Their Involvement in Lung Adenocarcinomas

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-...

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Autores principales: Sudhir, Putty-Reddy, Hsu, Chia-Lang, Wang, Mei-Jung, Wang, Yi-Ting, Chen, Yu-Ju, Sung, Ting-Yi, Hsu, Wen-Lian, Yang, Ueng-Cheng, Chen, Jeou-Yuan
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102680/
https://www.ncbi.nlm.nih.gov/pubmed/21637843
http://dx.doi.org/10.1371/journal.pone.0020199
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author Sudhir, Putty-Reddy
Hsu, Chia-Lang
Wang, Mei-Jung
Wang, Yi-Ting
Chen, Yu-Ju
Sung, Ting-Yi
Hsu, Wen-Lian
Yang, Ueng-Cheng
Chen, Jeou-Yuan
author_facet Sudhir, Putty-Reddy
Hsu, Chia-Lang
Wang, Mei-Jung
Wang, Yi-Ting
Chen, Yu-Ju
Sung, Ting-Yi
Hsu, Wen-Lian
Yang, Ueng-Cheng
Chen, Jeou-Yuan
author_sort Sudhir, Putty-Reddy
collection PubMed
description 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.
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spelling pubmed-31026802011-06-02 Phosphoproteomics Identifies Oncogenic Ras Signaling Targets and Their Involvement in Lung Adenocarcinomas Sudhir, Putty-Reddy Hsu, Chia-Lang Wang, Mei-Jung Wang, Yi-Ting Chen, Yu-Ju Sung, Ting-Yi Hsu, Wen-Lian Yang, Ueng-Cheng Chen, Jeou-Yuan PLoS One Research Article 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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. Public Library of Science 2011-05-26 /pmc/articles/PMC3102680/ /pubmed/21637843 http://dx.doi.org/10.1371/journal.pone.0020199 Text en Sudhir et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sudhir, Putty-Reddy
Hsu, Chia-Lang
Wang, Mei-Jung
Wang, Yi-Ting
Chen, Yu-Ju
Sung, Ting-Yi
Hsu, Wen-Lian
Yang, Ueng-Cheng
Chen, Jeou-Yuan
Phosphoproteomics Identifies Oncogenic Ras Signaling Targets and Their Involvement in Lung Adenocarcinomas
title Phosphoproteomics Identifies Oncogenic Ras Signaling Targets and Their Involvement in Lung Adenocarcinomas
title_full Phosphoproteomics Identifies Oncogenic Ras Signaling Targets and Their Involvement in Lung Adenocarcinomas
title_fullStr Phosphoproteomics Identifies Oncogenic Ras Signaling Targets and Their Involvement in Lung Adenocarcinomas
title_full_unstemmed Phosphoproteomics Identifies Oncogenic Ras Signaling Targets and Their Involvement in Lung Adenocarcinomas
title_short Phosphoproteomics Identifies Oncogenic Ras Signaling Targets and Their Involvement in Lung Adenocarcinomas
title_sort phosphoproteomics identifies oncogenic ras signaling targets and their involvement in lung adenocarcinomas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102680/
https://www.ncbi.nlm.nih.gov/pubmed/21637843
http://dx.doi.org/10.1371/journal.pone.0020199
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