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Clinical Lung Cancer January 2019 - e7 Resource
Analysis of the Human Kinome and Phosphatome by Mass Cytometry Reveals Overexpression-Induced Effects on Cancer-Related Signaling
Graphical Abstract Authors
Xiao-Kang Lun, Damian Szklarczyk, Attila Ga´bor, ..., Julio Saez-Rodriguez, Christian von Mering, Bernd Bodenmiller
Correspondence
[email protected]
In Brief
Lun et al. perform mass-cytometry-based single-cell analysis to study how the expression levels of 649 kinases and phosphatases affect the intracellular signaling network. They expand the functional classification of the kinome and phosphatome based on abundance-dependent effects and identify novel signaling mechanisms underlying overexpression-driven diseases and drug resistance.
Highlights
d Human kinome- and phosphatome-wide screen of overexpression-altered signaling network
d Classification of the kinome and phosphatome based on abundance-dependent effects
d Phosphatase overexpression sustains MAPK-ERK signaling by halting negative feedback
d SRC, FES, YES1, and BLK lead to drug resistance in BRAF-MEK combined inhibition
Molecular Cell Resource
Analysis of the Human Kinome and Phosphatome by Mass Cytometry Reveals Overexpression-Induced Effects on Cancer-Related Signaling
Xiao-Kang Lun,1,2,7 Damian Szklarczyk,1,9 Attila Ga´bor,3,9 Nadine Dobberstein,1 Vito Riccardo Tomaso Zanotelli,1,4,8 Julio Saez-Rodriguez,3,5,6,10 Christian von Mering,1,10 and Bernd Bodenmiller1,8,11,* 1Institute of Molecular Life Sciences, University of Zurich,€ 8057 Zurich,€ Switzerland 2Molecular Life Sciences PhD Program, Life Science Zurich€ Graduate School, ETH Zurich€ and University of Zurich,€ 8057 Zurich,€ Switzerland 3Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany 4Systems Biology PhD Program, Life Science Zurich€ Graduate School, ETH Zurich€ and University of Zurich,€ 8057 Zurich,€ Switzerland 5European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI), Hinxton, CB10 1SD Cambridge, UK 6Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, BIOQUANT, 69120 Heidelberg, Germany 7Present address: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA 8Present address: Department of Quantitative Biomedicine, University of Zurich,€ 8057 Zurich,€ Switzerland 9These authors contributed equally 10These authors contributed equally 11Lead Contact *Correspondence: [email protected]
SUMMARY
Kinase and phosphatase overexpression drives tumorigenesis and drug resistance. We previously developed a mass-cytometry-based single-cell prote-omics approach that enables quantitative assessment of overexpression effects on cell signaling. Here, we applied this approach in a human kinome- and phos-phatome-wide study to assess how 649 individually overexpressed proteins modulated cancer-related signaling in HEK293T cells in an abundance-depen-dent manner. Based on these data, we expanded the functional classification of human kinases and phosphatases and showed that the overexpression effects include non-catalytic roles. We detected 208 previously unreported signaling relationships. The signaling dynamics analysis indicated that the overex-pression of ERK-specific phosphatases sustains proliferative signaling. This suggests a phosphatase-driven mechanism of cancer progression. Moreover, our analysis revealed a drug-resistant mechanism through which overexpression of tyrosine kinases, including SRC, FES, YES1, and BLK, induced MEK-in-dependent ERK activation in melanoma A375 cells. These proteins could predict drug sensitivity to BRAF-MEK concurrent inhibition in cells carrying BRAF mutations.