Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling

Pau Creixell; Erwin M Schoof; Craig D Simpson; James Longden; Chad J Miller; Hua Jane Lou; Lara Perryman; Thomas R Cox; Nevena Zivanovic; Antonio Palmeri; Agata Wesolowska-Andersen; Manuela Helmer-Citterich; Jesper Ferkinghoff-Borg; Hiroaki Itamochi; Bernd Bodenmiller; Janine T Erler; Benjamin E Turk; Rune Linding

doi:10.1016/j.cell.2015.08.056

Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling

Pau Creixell, Erwin M Schoof, Craig D Simpson, James Longden, Chad J Miller, Hua Jane Lou, Lara Perryman, Thomas R Cox, Nevena Zivanovic, Antonio Palmeri, Agata Wesolowska-Andersen, Manuela Helmer-Citterich, Jesper Ferkinghoff-Borg, Hiroaki Itamochi, Bernd Bodenmiller, Janine T Erler, Benjamin E Turk, Rune Linding

Theoretical high energy, astroparticle and gravitational physics

102 Citations (Scopus)

Abstract

Summary 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.

Original language	English
Journal	Cell
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2015.08.056
Publication status	Published - 24 Sept 2015

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Creixell, P., Schoof, E. M., Simpson, C. D., Longden, J., Miller, C. J., Lou, H. J., Perryman, L., Cox, T. R., Zivanovic, N., Palmeri, A., Wesolowska-Andersen, A., Helmer-Citterich, M., Ferkinghoff-Borg, J., Itamochi, H., Bodenmiller, B., Erler, J. T., Turk, B. E., & Linding, R. (2015). Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling. Cell. https://doi.org/10.1016/j.cell.2015.08.056

Creixell, P, Schoof, EM, Simpson, CD, Longden, J, Miller, CJ, Lou, HJ, Perryman, L, Cox, TR, Zivanovic, N, Palmeri, A, Wesolowska-Andersen, A, Helmer-Citterich, M, Ferkinghoff-Borg, J, Itamochi, H, Bodenmiller, B, Erler, JT, Turk, BE & Linding, R 2015, 'Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling', Cell. https://doi.org/10.1016/j.cell.2015.08.056

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title = "Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling",

abstract = "Summary 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.",

author = "Pau Creixell and Schoof, {Erwin M} and Simpson, {Craig D} and James Longden and Miller, {Chad J} and Lou, {Hua Jane} and Lara Perryman and Cox, {Thomas R} and Nevena Zivanovic and Antonio Palmeri and Agata Wesolowska-Andersen and Manuela Helmer-Citterich and Jesper Ferkinghoff-Borg and Hiroaki Itamochi and Bernd Bodenmiller and Erler, {Janine T} and Turk, {Benjamin E} and Rune Linding",

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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

PY - 2015/9/24

Y1 - 2015/9/24

N2 - Summary 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 - Summary 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

SN - 0092-8674

JO - Cell

JF - Cell

ER -

Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling

Abstract

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