Integration of multiple signaling pathway activities resolves K-RAS/N-RAS mutation paradox in colon epithelial cell response to inflammatory cytokine stimulation
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Kreeger Integr Biol 2010.pdf
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Author(s)
Kreeger, Pamela K.
Wang, Yufang
Haigis, Kevin M.
Lauffenburger, Douglas A
Date Issued
March 2010
Journal
Integrative Biology
Publisher
Royal Society of Chemistry
Citation
Kreeger, Pamela K. et al. “Integration of multiple signaling pathway activities resolves K-RAS/N-RAS mutation paradox in colon epithelial cell response to inflammatory cytokine stimulation.” Integrative Biology 2.4 (2010): 202.
Version
Final published version
Abstract
Colon tumors frequently harbor mutation in K-RAS and/or N-RAS, members of a GTPase family operating as a central hub for multiple key signaling pathways. While these proteins are strongly homologous, they exhibit diverse downstream effects on cell behavior. Utilizing an isogenic panel of human colon carcinoma cells bearing oncogenic mutations in K-RAS and/or N-RAS, we observed that K-RAS and double mutants similarly yield elevated apoptosis in response to treatment with TNFα compared to N-RAS mutants. Regardless, and in surprising contrast, key phospho-protein signals were more similar between N-RAS and dual mutants. This apparent contradiction could not be explained by any of the key signals individually, but a multi-pathway model constructed from the single-mutant cell line data was able to predict the behavior of the dual-mutant cell line. This success arises from a quantitative integration of multiple pro-apoptotic (pIκBα, pERK2) and pro-survival (pJNK, pHSP27) signals in manner not easily discerned from intuitive inspection.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1039/B925935J
