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

• Published in: Nature communications Vol. 11; no. 1; pp. 1 - 14
• Main Authors: Kennedy, Susan A., Jarboui, Mohamed-Ali, Srihari, Sriganesh, Raso, Cinzia, Bryan, Kenneth, Dernayka, Layal, Charitou, Theodosia, Bernal-Llinares, Manuel, Herrera-Montavez, Carlos, Krstic, Aleksandar, Matallanas, David, Kotlyar, Max, Jurisica, Igor, Curak, Jasna, Wong, Victoria, Stagljar, Igor, LeBihan, Thierry, Imrie, Lisa, Pillai, Priyanka, Lynn, Miriam A., Fasterius, Erik, Al-Khalili Szigyarto, Cristina, Breen, James, Kiel, Christina, Serrano, Luis, Rauch, Nora, Rukhlenko, Oleksii, Kholodenko, Boris N., Iglesias-Martinez, Luis F., Ryan, Colm J., Pilkington, Ruth, Cammareri, Patrizia, Sansom, Owen, Shave, Steven, Auer, Manfred, Horn, Nicola, Klose, Franziska, Ueffing, Marius, Boldt, Karsten, Lynn, David J., Kolch, Walter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/31; 38/1; 38/23; 45/23; 45/91; 631/45/475/2290; 631/553/1806; 631/67/395; 82/1; 82/58; 96/1; 96/106; 96/109; 96/2; 96/31; 96/95; Biological activity; Cancer; Colorectal cancer; Colorectal carcinoma; Epidermal growth factor; Epidermal growth factor receptors; Gene mapping; Gene regulation; Genetic analysis; Growth factors; Humanities and Social Sciences; K-Ras protein; Levels; Mapping; Mathematical analysis; Mathematical models; multidisciplinary; Mutation; Phenotypes; Phosphorylation; Protein composition; Proteins; Science; Science (multidisciplinary); Signal transduction; Signaling; Structure-function relationships; Transcription; Wiring
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14224-9

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. Kras is often mutated in colorectal cancer but how this oncogenic mutation alters signalling pathways globally is undetermined. Here, the authors analyse how this mutation affects protein interaction networks and signal flow showing an extensive re‐wiring of signalling in response to KRas mutation