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Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation

Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize the global impact of an oncogen...

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Autores principales: Ma, Xiuquan, Zhang, Luxi, Song, Jiangning, Nguyen, Elizabeth, Lee, Rachel S., Rodgers, Samuel J., Li, Fuyi, Huang, Cheng, Schittenhelm, Ralf B., Chan, Howard, Chheang, Chanly, Wu, Jianmin, Brown, Kristin K., Mitchell, Christina A., Simpson, Kaylene J., Daly, Roger J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336867/
https://www.ncbi.nlm.nih.gov/pubmed/30655532
http://dx.doi.org/10.1038/s41467-018-08154-1
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author Ma, Xiuquan
Zhang, Luxi
Song, Jiangning
Nguyen, Elizabeth
Lee, Rachel S.
Rodgers, Samuel J.
Li, Fuyi
Huang, Cheng
Schittenhelm, Ralf B.
Chan, Howard
Chheang, Chanly
Wu, Jianmin
Brown, Kristin K.
Mitchell, Christina A.
Simpson, Kaylene J.
Daly, Roger J.
author_facet Ma, Xiuquan
Zhang, Luxi
Song, Jiangning
Nguyen, Elizabeth
Lee, Rachel S.
Rodgers, Samuel J.
Li, Fuyi
Huang, Cheng
Schittenhelm, Ralf B.
Chan, Howard
Chheang, Chanly
Wu, Jianmin
Brown, Kristin K.
Mitchell, Christina A.
Simpson, Kaylene J.
Daly, Roger J.
author_sort Ma, Xiuquan
collection PubMed
description Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotate the regulated kinases. As an example, we identify 63 protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells. An integrated siRNA screen identifies nine kinases, including SGK1, as being essential for Src-induced transformation. Accordingly, we find that Src positively regulates SGK1 expression in triple negative breast cancer cells, which exhibit a prominent signalling network governed by Src family kinases. Furthermore, combined inhibition of Src and SGK1 reduces colony formation and xenograft growth more effectively than either treatment alone. Therefore, this approach not only provides mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies.
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spelling pubmed-63368672019-01-22 Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation Ma, Xiuquan Zhang, Luxi Song, Jiangning Nguyen, Elizabeth Lee, Rachel S. Rodgers, Samuel J. Li, Fuyi Huang, Cheng Schittenhelm, Ralf B. Chan, Howard Chheang, Chanly Wu, Jianmin Brown, Kristin K. Mitchell, Christina A. Simpson, Kaylene J. Daly, Roger J. Nat Commun Article Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotate the regulated kinases. As an example, we identify 63 protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells. An integrated siRNA screen identifies nine kinases, including SGK1, as being essential for Src-induced transformation. Accordingly, we find that Src positively regulates SGK1 expression in triple negative breast cancer cells, which exhibit a prominent signalling network governed by Src family kinases. Furthermore, combined inhibition of Src and SGK1 reduces colony formation and xenograft growth more effectively than either treatment alone. Therefore, this approach not only provides mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies. Nature Publishing Group UK 2019-01-17 /pmc/articles/PMC6336867/ /pubmed/30655532 http://dx.doi.org/10.1038/s41467-018-08154-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ma, Xiuquan
Zhang, Luxi
Song, Jiangning
Nguyen, Elizabeth
Lee, Rachel S.
Rodgers, Samuel J.
Li, Fuyi
Huang, Cheng
Schittenhelm, Ralf B.
Chan, Howard
Chheang, Chanly
Wu, Jianmin
Brown, Kristin K.
Mitchell, Christina A.
Simpson, Kaylene J.
Daly, Roger J.
Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation
title Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation
title_full Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation
title_fullStr Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation
title_full_unstemmed Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation
title_short Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation
title_sort characterization of the src-regulated kinome identifies sgk1 as a key mediator of src-induced transformation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336867/
https://www.ncbi.nlm.nih.gov/pubmed/30655532
http://dx.doi.org/10.1038/s41467-018-08154-1
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