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Cell. 2015 Sep 24;163(1):202-17. doi: 10.1016/j.cell.2015.08.056. Epub 2015 Sep 17.

Kinome-wide decoding of network-attacking mutations rewiring cancer signaling.

Author information

1
Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.
2
Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark.
3
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
5
Centre for Molecular Bioinformatics, University of Rome Tor Vergata, 00133 Rome, Italy.
6
Tottori University School of Medicine, Yonago 683-8504, Japan.
7
Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark. Electronic address: linding@lindinglab.org.

Abstract

Cancer cells acquire pathological phenotypes through accumulation of mutations that perturb signaling networks. 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 developed a computational platform (ReKINect) to identify NAMs and systematically interpreted the exomes and quantitative (phospho-)proteomes of five ovarian cancer cell lines and the global cancer genome repository. 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. We discover mutant molecular logic gates, a drift toward phospho-threonine signaling, weakening of phosphorylation motifs, and kinase-inactivating hotspots in cancer. Our method pinpoints functional NAMs, scales with the complexity of cancer genomes and cell signaling, and may enhance our capability to therapeutically target tumor-specific networks.

PMID:
26388441
PMCID:
PMC4644236
DOI:
10.1016/j.cell.2015.08.056
[Indexed for MEDLINE]
Free PMC Article

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