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dc.contributor.authorHuang, Lu
dc.contributor.authorPan, Catherine Qiurong
dc.contributor.authorLi, Baowen
dc.contributor.authorTucker-Kellogg, Lisa
dc.contributor.authorTidor, Bruce
dc.contributor.authorChen, Yu Zong
dc.contributor.authorLow, Boon Chuan
dc.date.accessioned2011-11-10T14:54:21Z
dc.date.available2011-11-10T14:54:21Z
dc.date.issued2011-08
dc.date.submitted2011-02
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/1721.1/66997
dc.description.abstractERK activation is enhanced by the scaffolding proteins KSR and MP1, localized near the cell membrane and late endosomes respectively, but little is known about their dynamic interplay. We develop here a mathematical model with ordinary differential equations to describe the dynamic activation of EGFR-ERK signaling under a conventional pathway without scaffolds, a KSR-scaffolded pathway, and an MP1-scaffolded pathway, and their impacts were examined under the influence of the endosomal regulators, Cbl-CIN85 and Endophilin A1. This new integrated model, validated against experimental results and computational constraints, shows that changes of ERK activation and EGFR endocytosis in response to EGF concentrations (i.e ligand sensitivity) depend on these scaffold proteins and regulators. The KSR-scaffolded and the conventional pathways act synergistically and are sensitive to EGF stimulation. When the KSR level is high, the sensitivity of ERK activation from this combined pathway remains low when Cbl-CIN85 level is low. But, such sensitivity can be increased with increasing levels of Endophilin if Cbl-CIN85 level becomes high. However, reduced KSR levels already present high sensitivity independent of Endophilin levels. In contrast, ERK activation by MP1 is additive to that of KSR but it shows little ligand-sensitivity under high levels of EGF. This can be partly reversed by increasing level of Endophilin while keeping Cbl-CIN85 level low. Further analyses showed that high levels of KSR affect ligand-sensitivity of EGFR endocytosis whereas MP1 ensures the robustness of endosomal ERK activation. These simulations constitute a multi-dimensional exploration of how EGF-dependent EGFR endocytosis and ERK activation are dynamically affected by scaffolds KSR and MP1, co-regulated by Cbl-CIN85 and Endophilin A1. Together, these results provide a detailed and quantitative demonstration of how regulators and scaffolds can collaborate to fine-tune the ligand-dependent sensitivity of EGFR endocytosis and ERK activation which could underlie differences during normal physiology, disease states and drug responses.en_US
dc.description.sponsorshipSingapore-MIT Alliance for Research and Technologyen_US
dc.description.sponsorshipNational University of Singapore (Academic Research Fund (R-148-000-081-112/101))en_US
dc.description.sponsorshipSingapore. National Research Foundationen_US
dc.description.sponsorshipSingapore. Ministry of Educationen_US
dc.language.isoen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.pone.0022933en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/en_US
dc.sourcePLoSen_US
dc.titleSimulating EGFR-ERK Signaling Control by Scaffold Proteins KSR and MP1 Reveals Differential Ligand-Sensitivity Co-Regulated by Cbl-CIN85 and Endophilinen_US
dc.typeArticleen_US
dc.identifier.citationHuang, Lu et al. “Simulating EGFR-ERK Signaling Control by Scaffold Proteins KSR and MP1 Reveals Differential Ligand-Sensitivity Co-Regulated by Cbl-CIN85 and Endophilin.” Ed. Sudha Agarwal. PLoS ONE 6 (2011): e22933.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratoryen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Electrical Engineering and Computer Scienceen_US
dc.contributor.departmentSingapore-MIT Alliance in Research and Technology (SMART)en_US
dc.contributor.departmentSingapore-MIT Alliance in Research and Technology (SMART)en_US
dc.contributor.approverTidor, Bruce
dc.contributor.mitauthorTidor, Bruce
dc.contributor.mitauthorHuang, Lu
dc.contributor.mitauthorTucker-Kellogg, Lisa
dc.contributor.mitauthorChen, Yu Zong
dc.contributor.mitauthorLow, Boon Chuan
dc.relation.journalPLoS ONEen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsHuang, Lu; Pan, Catherine Qiurong; Li, Baowen; Tucker-Kellogg, Lisa; Tidor, Bruce; Chen, Yuzong; Low, Boon Chuanen
dc.identifier.orcidhttps://orcid.org/0000-0002-3320-3969
mit.licensePUBLISHER_CCen_US
mit.metadata.statusComplete


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