期刊
MOLECULAR CELL
卷 74, 期 5, 页码 1086-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2019.04.021
关键词
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资金
- Swiss National Science Foundation (SNSF) R'Equip grant
- SNSF Assistant Professorship grant [PP00P3-144874]
- European Research Council (ERC) under the European Union's Seventh Framework Program (FP/2007-2013)/ERC Grant [336921]
- NIH [UC4 DK108132]
- Swiss National Science Foundation (SNF) [PP00P3_144874] Funding Source: Swiss National Science Foundation (SNF)
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 phosphatasedriven 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.
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