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

• DOI: 10.1016/j.molcel.2019.04.021
• Publication Date: 2019-05-14T14:30:02Z
• Authors: Xiao-Kang Lun; Damian Szklarczyk; Attila Gábor; Nadine Dobberstein; Vito Riccardo Tom...; Julio Saez-Rodriguez; Christian von Mering; Bernd Bodenmiller
• Keywords: Kinome; Mass cytometry

ISSN:1097-2765<br/>ISSN:1097-4164<br/>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.<br/>Molecular Cell, 74 (5)<br/>