Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

Susan A. Kennedy; Mohamed Ali Jarboui; Sriganesh Srihari; Cinzia Raso; Kenneth Bryan; Layal Dernayka; Theodosia Charitou; Manuel Bernal-Llinares; Carlos Herrera-Montavez; Aleksandar Krstic; David Matallanas; Max Kotlyar; Igor Jurisica; Jasna Curak; Victoria Wong; Igor Stagljar; Thierry LeBihan; Lisa Imrie; Priyanka Pillai; Miriam A. Lynn; Erik Fasterius; Cristina Al-Khalili Szigyarto; James Breen; Christina Kiel; Luis Serrano; Nora Rauch; Oleksii Rukhlenko; Boris N. Kholodenko; Luis F. Iglesias-Martinez; Colm J. Ryan; Ruth Pilkington; Patrizia Cammareri; Owen Sansom; Steven Shave; Manfred Auer; Nicola Horn; Franziska Klose; Marius Ueffing; Karsten Boldt; David J. Lynn; Walter Kolch

doi:10.1038/s41467-019-14224-9

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS^G13D

Susan A. Kennedy, Mohamed Ali Jarboui, Sriganesh Srihari, Cinzia Raso, Kenneth Bryan, Layal Dernayka, Theodosia Charitou, Manuel Bernal-Llinares, Carlos Herrera-Montavez, Aleksandar Krstic, David Matallanas, Max Kotlyar, Igor Jurisica, Jasna Curak, Victoria Wong, Igor Stagljar, Thierry LeBihan, Lisa Imrie, Priyanka Pillai, Miriam A. LynnErik Fasterius, Cristina Al-Khalili Szigyarto, James Breen, Christina Kiel, Luis Serrano, Nora Rauch, Oleksii Rukhlenko, Boris N. Kholodenko, Luis F. Iglesias-Martinez, Colm J. Ryan, Ruth Pilkington, Patrizia Cammareri, Owen Sansom, Steven Shave, Manfred Auer, Nicola Horn, Franziska Klose, Marius Ueffing, Karsten Boldt, David J. Lynn, Walter Kolch

College of Medicine and Public Health

Research output: Contribution to journal › Article › peer-review

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Abstract

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRAS^G13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRAS^G13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.

Original language	English
Article number	499
Number of pages	14
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-019-14224-9
Publication status	Published - 24 Jan 2020

Bibliographical note

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Keywords

Protein-protein-interaction networks
oncogenic mutations
Epidermal growth factor receptor network
colorectal cancer cells
Phosphorylation

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-14224-9Licence: CC BY

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Cite this

Kennedy, S. A., Jarboui, M. A., Srihari, S., Raso, C., Bryan, K., Dernayka, L., Charitou, T., Bernal-Llinares, M., Herrera-Montavez, C., Krstic, A., Matallanas, D., Kotlyar, M., Jurisica, I., Curak, J., Wong, V., Stagljar, I., LeBihan, T., Imrie, L., Pillai, P., ... Kolch, W. (2020). Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS^G13D. Nature Communications, 11, Article 499. https://doi.org/10.1038/s41467-019-14224-9

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title = "Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D",

abstract = "Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.",

keywords = "Protein-protein-interaction networks, oncogenic mutations, Epidermal growth factor receptor network, colorectal cancer cells, Phosphorylation",

author = "Kennedy, {Susan A.} and Jarboui, {Mohamed Ali} and Sriganesh Srihari and Cinzia Raso and Kenneth Bryan and Layal Dernayka and Theodosia Charitou and Manuel Bernal-Llinares and Carlos Herrera-Montavez and Aleksandar Krstic and David Matallanas and Max Kotlyar and Igor Jurisica and Jasna Curak and Victoria Wong and Igor Stagljar and Thierry LeBihan and Lisa Imrie and Priyanka Pillai and Lynn, {Miriam A.} and Erik Fasterius and {Al-Khalili Szigyarto}, Cristina and James Breen and Christina Kiel and Luis Serrano and Nora Rauch and Oleksii Rukhlenko and Kholodenko, {Boris N.} and Iglesias-Martinez, {Luis F.} and Ryan, {Colm J.} and Ruth Pilkington and Patrizia Cammareri and Owen Sansom and Steven Shave and Manfred Auer and Nicola Horn and Franziska Klose and Marius Ueffing and Karsten Boldt and Lynn, {David J.} and Walter Kolch",

note = "Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.",

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Kennedy, SA, Jarboui, MA, Srihari, S, Raso, C, Bryan, K, Dernayka, L, Charitou, T, Bernal-Llinares, M, Herrera-Montavez, C, Krstic, A, Matallanas, D, Kotlyar, M, Jurisica, I, Curak, J, Wong, V, Stagljar, I, LeBihan, T, Imrie, L, Pillai, P, Lynn, MA, Fasterius, E, Al-Khalili Szigyarto, C, Breen, J, Kiel, C, Serrano, L, Rauch, N, Rukhlenko, O, Kholodenko, BN, Iglesias-Martinez, LF, Ryan, CJ, Pilkington, R, Cammareri, P, Sansom, O, Shave, S, Auer, M, Horn, N, Klose, F, Ueffing, M, Boldt, K, Lynn, DJ & Kolch, W 2020, 'Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS^G13D', Nature Communications, vol. 11, 499. https://doi.org/10.1038/s41467-019-14224-9

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T1 - Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

AU - Kennedy, Susan A.

AU - Jarboui, Mohamed Ali

AU - Srihari, Sriganesh

AU - Raso, Cinzia

AU - Bryan, Kenneth

AU - Dernayka, Layal

AU - Charitou, Theodosia

AU - Bernal-Llinares, Manuel

AU - Herrera-Montavez, Carlos

AU - Krstic, Aleksandar

AU - Matallanas, David

AU - Kotlyar, Max

AU - Jurisica, Igor

AU - Curak, Jasna

AU - Wong, Victoria

AU - Stagljar, Igor

AU - LeBihan, Thierry

AU - Imrie, Lisa

AU - Pillai, Priyanka

AU - Lynn, Miriam A.

AU - Fasterius, Erik

AU - Al-Khalili Szigyarto, Cristina

AU - Breen, James

AU - Kiel, Christina

AU - Serrano, Luis

AU - Rauch, Nora

AU - Rukhlenko, Oleksii

AU - Kholodenko, Boris N.

AU - Iglesias-Martinez, Luis F.

AU - Ryan, Colm J.

AU - Pilkington, Ruth

AU - Cammareri, Patrizia

AU - Sansom, Owen

AU - Shave, Steven

AU - Auer, Manfred

AU - Horn, Nicola

AU - Klose, Franziska

AU - Ueffing, Marius

AU - Boldt, Karsten

AU - Lynn, David J.

AU - Kolch, Walter

N1 - Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PY - 2020/1/24

Y1 - 2020/1/24

N2 - Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.

AB - Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.

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KW - oncogenic mutations

KW - Epidermal growth factor receptor network

KW - colorectal cancer cells

KW - Phosphorylation

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