Kinome-wide decoding of network-attacking mutations rewiring cancer signaling.
Bottom Line: However, global analysis of these events is currently limited.Here, we identify six types of network-attacking mutations (NAMs), including changes in kinase and SH2 modulation, network rewiring, and the genesis and extinction of phosphorylation sites.We identified and experimentally validated several NAMs, including PKCγ M501I and PKD1 D665N, which encode specificity switches analogous to the appearance of kinases de novo within the kinome.
Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.Show MeSH
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Mentions: In order to experimentally investigate NAMs, we performed a global integrative analysis by combining exome next-generation sequencing (NGS) and quantitative mass spectrometry (MS)-based (phospho-)proteomics on a set of five ovarian cancer cell lines (ES2, OVAS, OVISE, TOV-21, and KOC-7C; Figures S1 and S2) and conducted genome-specific proteomics analyses (Experimental Procedures). By following a Spike-in SILAC-based labeling strategy (Geiger et al., 2011) (Figures S1 and S2; Experimental Procedures), we could identify and accurately quantify on average more than 6,000 unique phosphorylation sites across over 2,000 proteins in each of the five cell lines. Furthermore, NGS identified close to 9,000 unique missense variants per cell line (including SNPs and germline mutations as well as somatic mutations) that were subsequently interpreted by ReKINect (Figure 2).
Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.