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

Xiuquan Ma, Luxi Zhang, Jiangning Song, Elizabeth Nguyen, Rachel S. Lee, Samuel J. Rodgers, Fuyi Li, Cheng Huang, Ralf B. Schittenhelm, Howard Chan, Chanly Chheang, Jianmin Wu, Kristin K. Brown, Christina A. Mitchell, Kaylene J. Simpson, Roger J. Daly

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Article number296
Number of pages16
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 17 Jan 2019

Keywords

  • cell signalling
  • kinases
  • oncogenes
  • proteomics

Cite this

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title = "Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation",
abstract = "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.",
keywords = "cell signalling, kinases, oncogenes, proteomics",
author = "Xiuquan Ma and Luxi Zhang and Jiangning Song and Elizabeth Nguyen and Lee, {Rachel S.} and Rodgers, {Samuel J.} and Fuyi Li and Cheng Huang and Schittenhelm, {Ralf B.} and Howard Chan and Chanly Chheang and Jianmin Wu and Brown, {Kristin K.} and Mitchell, {Christina A.} and Simpson, {Kaylene J.} and Daly, {Roger J.}",
year = "2019",
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doi = "10.1038/s41467-018-08154-1",
language = "English",
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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.

In: Nature Communications, Vol. 10, No. 1, 296, 17.01.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation

AU - Ma, Xiuquan

AU - Zhang, Luxi

AU - Song, Jiangning

AU - Nguyen, Elizabeth

AU - Lee, Rachel S.

AU - Rodgers, Samuel J.

AU - Li, Fuyi

AU - Huang, Cheng

AU - Schittenhelm, Ralf B.

AU - Chan, Howard

AU - Chheang, Chanly

AU - Wu, Jianmin

AU - Brown, Kristin K.

AU - Mitchell, Christina A.

AU - Simpson, Kaylene J.

AU - Daly, Roger J.

PY - 2019/1/17

Y1 - 2019/1/17

N2 - 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.

AB - 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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