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dc.contributor.authorFujita, Yoshihisaja
dc.contributor.authorKomatsu, Naokija
dc.contributor.authorMatsuda, Michiyukija
dc.contributor.authorAoki, Kazuhiroja
dc.contributor.alternative青木, 一洋ja
dc.description.abstractThe Ras-ERK and PI3K-mTOR pathways are hyperactivated in various malignant tumors. Feedforward (FF) and feedback (FB) regulations between the Ras-ERK and the PI3K-mTOR pathways have been suggested to attenuate sensitivity to drugs targeting these pathways and confer tumor resistance to therapies. However, because analyses of such regulations require measurements and perturbations with high temporal resolution, the quantitative roles played by FF and FB regulations in the intrinsic resistance to molecular targeting drugs still remain unclear. To address this issue, we quantified FF and FB regulations of the epidermal growth factor receptor (EGFR) signaling pathway by Förster/fluorescence resonance energy transfer (FRET) imaging. EGF-induced activation of EGFR, Ras, extracellular-signal-regulated kinase and S6K with or without inhibitors was measured by FRET imaging, and analyzed by semi-automatic image processing. Based on the imaging data set and kinetic parameters determined by our previous studies, we identified the roles played by a coherent FF regulation and two negative FB regulations, one of which was not recognized previously. The systems analyses revealed how these FF and FB regulations shape the temporal dynamics of extracellular-signal-regulated kinase activity upon EGF stimulation. Furthermore, the simulation model predicts the response of molecular targeting drugs applied solely or in combination with each other to BRaf- or KRas-mutated cancer cell lines, indicating the validity of a quantitative model integrating FF and FB regulations.ja
dc.rightsThis is the peer reviewed version of the following article: Fujita, Y., Komatsu, N., Matsuda, M. and Aoki, K. (2014), Fluorescence resonance energy transfer based quantitative analysis of feedforward and feedback loops in epidermal growth factor receptor signaling and the sensitivity to molecular targeting drugs. FEBS Journal, 281: 3177–3192, which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.ja
dc.rightsこの論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。This is not the published version. Please cite only the published version.ja
dc.subject.meshDrug Delivery Systemsja
dc.subject.meshExtracellular Signal-Regulated MAP Kinases/metabolismja
dc.subject.meshFeedback, Physiological/physiologyja
dc.subject.meshFluorescence Resonance Energy Transferja
dc.subject.meshHeLa Cellsja
dc.subject.meshMAP Kinase Signaling System/physiologyja
dc.subject.meshMonomeric GTP-Binding Proteins/physiologyja
dc.subject.meshPhosphatidylinositol 3-Kinases/physiologyja
dc.subject.meshProto-Oncogene Proteins B-raf/physiologyja
dc.subject.meshProto-Oncogene Proteins c-akt/metabolismja
dc.subject.meshReceptor, Epidermal Growth Factor/physiologyja
dc.subject.meshRibosomal Protein S6 Kinases/physiologyja
dc.subject.meshSignal Transduction/physiologyja
dc.subject.meshSystems Biologyja
dc.subject.meshTOR Serine-Threonine Kinases/physiologyja
dc.titleFluorescence resonance energy transfer based quantitative analysis of feedforward and feedback loops in epidermal growth factor receptor signaling and the sensitivity to molecular targeting drugs.ja
dc.type.niitypeJournal Articleja
dc.identifier.jtitleThe FEBS journalja
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