Simulating EGFR-ERK Signaling Control by Scaffold Proteins KSR and MP1 Reveals Differential Ligand-Sensitivity Co-Regulated by Cbl-CIN85 and Endophilin 英文参考文献.docVIP

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Simulating EGFR-ERK Signaling Control by Scaffold Proteins KSR and MP1 Reveals Differential Ligand-Sensitivity Co-Regulated by Cbl-CIN85 and Endophilin 英文参考文献.doc

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Simulating EGFR-ERK Signaling Control by Scaffold Proteins KSR and MP1 Reveals Differential Ligand-Sensitivity Co-Regulated by Cbl-CIN85 and Endophilin 英文参考文献

SimulatingEGFR-ERKSignalingControlbyScaffold ProteinsKSRandMP1RevealsDifferentialLigand- SensitivityCo-RegulatedbyCbl-CIN85andEndophilin LuHuang1,7,CatherineQiurongPan5,7,BaowenLi6,LisaTucker-Kellogg1,7,BruceTidor1,3,4 ,Yuzong Chen1,2*,BoonChuanLow1,5,7 * 1Computational Systems Biology, Singapore-MIT Alliance, National University of Singapore, Singapore, Singapore, 2Department of Pharmacy, National University of Singapore, Singapore, Singapore, 3Department of Biological Engineering, Department of Electrical Engineering Computer Science, Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 4Singapore-MIT Alliance for Research and Technology, Singapore, Singapore, 5Department of Biological Sciences, National University of Singapore, Singapore, Singapore, 6Department of Physics, National UniversityofSingapore,Singapore,Singapore,7MechanobiologyInstitute,NationalUniversityofSingapore,Singapore,Singapore Abstract ERKactivationisenhancedbythescaffoldingproteinsKSRandMP1,localizednearthecellmembraneandlateendosomes 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,aKSR-scaffoldedpathway,andanMP1-scaffoldedpathway,andtheirimpactswereexaminedundertheinfluence 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 conventionalpathwaysactsynergisticallyandaresensitivetoEGFstimulation.WhentheKSRlevelishigh,thesensitivityof ERKactivationfromthiscombinedpathwayremainslowwhenCbl-CIN85levelislow.But,suchsens