Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells
| Autor: | Sara Sigismund, Fabrizio Capuani, Simona Polo, Alexia Conte, Luca Marchetti, Andrea Ciliberto, Pier Paolo Di Fiore, Corrado Priami, Elisabetta Argenzio |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Genetics and Molecular Biology (all)
EGFR ubiquitination ODE modeling EGFR phosphorylation EGFR ubiquitination deterministic simulation General Physics and Astronomy Enzyme-Linked Immunosorbent Assay Plasma protein binding Biology Models Biological Biochemistry General Biochemistry Genetics and Molecular Biology Article Physics and Astronomy (all) Mice Downregulation and upregulation Epidermal growth factor Animals Humans Computer Simulation Epidermal growth factor receptor Proto-Oncogene Proteins c-cbl Dynamic Modeling and simulation Phosphorylation Receptor GRB2 Adaptor Protein deterministic simulation Multidisciplinary Binding Sites Epidermal Growth Factor ODE modeling Chemistry (all) Ubiquitination Cooperative binding General Chemistry Molecular biology Cell biology ErbB Receptors Dynamic Modeling and simulation Biochemistry Genetics and Molecular Biology (all) Gene Expression Regulation biology.protein NIH 3T3 Cells EGFR phosphorylation GRB2 Densitometry HeLa Cells Protein Binding |
| Zdroj: | Nature Communications |
| Popis: | Ubiquitination of the epidermal growth factor receptor (EGFR) that occurs when Cbl and Grb2 bind to three phosphotyrosine residues (pY1045, pY1068 and pY1086) on the receptor displays a sharp threshold effect as a function of EGF concentration. Here we use a simple modelling approach together with experiments to show that the establishment of the threshold requires both the multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR. While the threshold is remarkably robust, a more sophisticated model predicted that it could be modulated as a function of EGFR levels on the cell surface. We confirmed experimentally that the system has evolved to perform optimally at physiological levels of EGFR. As a consequence, this system displays an intrinsic weakness that causes—at the supraphysiological levels of receptor and/or ligand associated with cancer—uncoupling of the mechanisms leading to signalling through phosphorylation and attenuation through ubiquitination. Cells respond to increasing concentrations of EGF by altering the balance between EGFR phosphorylation and ubiquitination. Here the authors show that the establishment of an EGFR signaling threshold requires both a multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR. |
| Databáze: | OpenAIRE |
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