期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-14224-9
关键词
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资金
- European Union FP7 Grant [278568]
- Science Foundation Ireland [14/IA/2395]
- SmartNanoTox [686098]
- NanoCommons [731032]
- MSCA-IF-2016 SAMNets [750688]
- Science Foundation Ireland Career Development award [15-CDA-3495]
- Canada Research Chair Program (CRC) [225404]
- Krembil Foundation
- Ontario Research Fund [GL2-01-030, 34876, ORF/DIG-501411, RE08-009]
- Natural Sciences Research Council (NSERC) [203475]
- Canada Foundation for Innovation (CFI) [225404, 30865]
- IBM
- EMBL Australia
- ERC investigator Award [ColonCan 311301]
- CRUK
- Canadian Cancer Society Research Institute [703889]
- Genome Canada via Ontario Genomics [9427, 9428]
- Consortium Quebecois sur la Decouverte du Medicament (CQDM Quantum Leap)
- Brain Canada (Quantum Leap)
- CQDM Explore
- OCE [23929]
- Teagasc Walsh Fellowship
- Tistou & Charlotte Kerstan Stiftung
- eResearch SA
- National Collaborative Research Infrastructure Strategy
- Science Foundation Ireland (SFI) [15/CDA/3495] Funding Source: Science Foundation Ireland (SFI)
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.
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