2. Academic Validation
  3. Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation

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

  • Nat Commun. 2019 Jan 17;10(1):296. doi: 10.1038/s41467-018-08154-1.
Xiuquan Ma 1 2,  Luxi Zhang 1 2,  Jiangning Song 2 3 4,  Elizabeth Nguyen 1 2,  Rachel S Lee 1 2,  Samuel J Rodgers 1 2,  Fuyi Li 2 3,  Cheng Huang 5,  Ralf B Schittenhelm 5,  Howard Chan 1 2,  Chanly Chheang 1 2,  Jianmin Wu 6,  Kristin K Brown 7 8 9,  Christina A Mitchell 1 2,  Kaylene J Simpson 9 10,  Roger J Daly 11 12
Affiliations

Affiliations

  • 1 Cancer Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
  • 2 Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia.
  • 3 Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
  • 4 Monash Centre for Data Science, Faculty of Information Technology, Monash University, Melbourne, VIC, 3800, Australia.
  • 5 Monash Biomedical Proteomics Facility and Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
  • 6 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
  • 7 Cancer Therapeutics Program and Cancer Metabolism Program, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
  • 8 Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC, 3010, Australia.
  • 9 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3010, Australia.
  • 10 Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
  • 11 Cancer Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia. [email protected].
  • 12 Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia. [email protected].
PMID: 30655532 DOI: 10.1038/s41467-018-08154-1
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.

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