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Mol Cell. 2019 Jun 6;74(5):1086-1102.e5. doi: 10.1016/j.molcel.2019.04.021. Epub 2019 May 14.

Analysis of the Human Kinome and Phosphatome by Mass Cytometry Reveals Overexpression-Induced Effects on Cancer-Related Signaling.

Author information

1
Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland; Molecular Life Sciences PhD Program, Life Science Zürich Graduate School, ETH Zürich and University of Zürich, 8057 Zürich, Switzerland.
2
Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland.
3
Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
4
Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland; Systems Biology PhD Program, Life Science Zürich Graduate School, ETH Zürich and University of Zürich, 8057 Zürich, Switzerland.
5
Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany; European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI), Hinxton, CB10 1SD Cambridge, UK; Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, BIOQUANT, 69120 Heidelberg, Germany.
6
Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland. Electronic address: bernd.bodenmiller@imls.uzh.ch.

Abstract

Kinase and phosphatase overexpression drives tumorigenesis and drug resistance. We previously developed a mass-cytometry-based single-cell proteomics approach that enables quantitative assessment of overexpression effects on cell signaling. Here, we applied this approach in a human kinome- and phosphatome-wide study to assess how 649 individually overexpressed proteins modulated cancer-related signaling in HEK293T cells in an abundance-dependent 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 overexpression 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-independent ERK activation in melanoma A375 cells. These proteins could predict drug sensitivity to BRAF-MEK concurrent inhibition in cells carrying BRAF mutations.

KEYWORDS:

BP-R(2) analysis; cancer signaling networks; drug resistance; functional classification; human kinome and phosphatome; mass cytometry; overexpression effects; signaling dynamics; signaling relationships; single-cell proteomics

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