Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling
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Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling. / Creixell, Pau; Schoof, Erwin M; Simpson, Craig D; Longden, James; Miller, Chad J; Lou, Hua Jane; Perryman, Lara; Cox, Thomas R; Zivanovic, Nevena; Palmeri, Antonio; Wesolowska-Andersen, Agata; Helmer-Citterich, Manuela; Ferkinghoff-Borg, Jesper; Itamochi, Hiroaki; Bodenmiller, Bernd; Erler, Janine T; Turk, Benjamin E; Linding, Rune.
In: Cell, 16.09.2015.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling
AU - Creixell, Pau
AU - Schoof, Erwin M
AU - Simpson, Craig D
AU - Longden, James
AU - Miller, Chad J
AU - Lou, Hua Jane
AU - Perryman, Lara
AU - Cox, Thomas R
AU - Zivanovic, Nevena
AU - Palmeri, Antonio
AU - Wesolowska-Andersen, Agata
AU - Helmer-Citterich, Manuela
AU - Ferkinghoff-Borg, Jesper
AU - Itamochi, Hiroaki
AU - Bodenmiller, Bernd
AU - Erler, Janine T
AU - Turk, Benjamin E
AU - Linding, Rune
N1 - Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2015/9/16
Y1 - 2015/9/16
N2 - 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.
AB - 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.
U2 - 10.1016/j.cell.2015.08.056
DO - 10.1016/j.cell.2015.08.056
M3 - Journal article
C2 - 26388441
JO - Cell
JF - Cell
SN - 0092-8674
ER -
ID: 144492952