Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783388134013140992 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6336867 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT maxiuquan characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT zhangluxi characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT songjiangning characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT nguyenelizabeth characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT leerachels characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT rodgerssamuelj characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT lifuyi characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT huangcheng characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT schittenhelmralfb characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT chanhoward characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT chheangchanly characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT wujianmin characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT brownkristink characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT mitchellchristinaa characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT simpsonkaylenej characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation AT dalyrogerj characterizationofthesrcregulatedkinomeidentifiessgk1asakeymediatorofsrcinducedtransformation |