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Reprogramming of the tyrosine kinase-regulated proteome in breast cancer by combined use of RNAi and SILAC quantitative proteomics

journal contribution
posted on 2023-06-08, 21:29 authored by Justin Stebbing, Hua Zhang, Yichen Xu, Arnhild Grothey, Paul Ajuh, Nicos Angelopoulos, Georgios GiamasGeorgios Giamas
Tyrosine kinases (TKs) are central regulators in cellular activities and perturbations of TK signaling contribute to oncogenesis. However, less than half of the TKs have been thoroughly studied and a global functional analysis of their proteomic portrait is lacking. Here we conducted a combined approach of RNAi and stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics to decode the TK-regulated proteome and associated signaling dynamics. As a result, a broad proteomic repertoire modulated by TKs was revealed, upon silencing of the 65 TKs expressed in MCF-7 breast cancer cells. This yielded 10 new distinctive TK clusters according to similarity in TK-regulated proteomes, each characterized by a unique signaling signature in contrast to previous classifications. We provide functional analyses and identify critical pathways for each cluster based on their common downstream targets. Analysis of different breast cancer subtypes demonstrated distinct correlations of each cluster with clinical outcome. From the significantly up- and down-regulated proteins, we identified a number of markers of drug sensitivity and resistance. These data supports the role of TKs in regulating major aspects of cellular activity, but also reveals redundancy in signalling, explaining why kinase inhibitors alone often fail to achieve their clinical aims. The TK-SILACepedia provides a comprehensive resource for studying the global function of TKs in cancer.


Publication status

  • Published


Molecular and Cellular Proteomics : MCP




American Society for Biochemistry and Molecular Biology



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Department affiliated with

  • Biochemistry Publications

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Peer reviewed?

  • Yes

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