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 and Roger J. Daly ()
Additional contact information
Xiuquan Ma: Monash University
Luxi Zhang: Monash University
Jiangning Song: Monash University
Elizabeth Nguyen: Monash University
Rachel S. Lee: Monash University
Samuel J. Rodgers: Monash University
Fuyi Li: Monash University
Cheng Huang: Monash University
Ralf B. Schittenhelm: Monash University
Howard Chan: Monash University
Chanly Chheang: Monash University
Jianmin Wu: Peking University Cancer Hospital & Institute
Kristin K. Brown: Peter MacCallum Cancer Centre
Christina A. Mitchell: Monash University
Kaylene J. Simpson: The University of Melbourne
Roger J. Daly: Monash University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08154-1

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