title: Computational analysis of the regulation of EGFR by protein tyrosine phosphatases.
abstract: The tyrosine phosphorylated epidermal growth factor receptor (EGFR) initiates numerous cell signaling pathways. Although EGFR phosphorylation levels are ultimately determined by the balance of receptor kinase and protein tyrosine phosphatase (PTP) activities, the kinetics of EGFR dephosphorylation are not well understood. Previous models of EGFR signaling have generally neglected PTP activity or computed PTP activity by considering data that do not fully reveal the kinetics and compartmentalization of EGFR dephosphorylation. We developed a compartmentalized, mechanistic model to elucidate the kinetics of EGFR dephosphorylation and the coupling of this process to phosphorylation-dependent EGFR endocytosis. Model regression against data from HeLa cells for EGFR phosphorylation response to EGFR activation, PTP inhibition, and EGFR kinase inhibition led to the conclusion that EGFR dephosphorylation occurs at the plasma membrane and in the cell interior with a timescale that is smaller than that for ligand-mediated EGFR endocytosis. The model further predicted that sufficiently rapid dephosphorylation of EGFR at the plasma membrane could potentially impede EGFR endocytosis, consistent with recent experimental findings. Overall, our results suggest that PTPs regulate multiple receptor-level phenomena via their action at the plasma membrane and cell interior and point to new possibilities for targeting PTPs for modulation of EGFR dynamics.
authors: Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, USA.
authors: Calixte S
authors: CS
authors: Monast
authors: Christopher M
authors: CM
authors: Furcht
authors: Matthew J
authors: MJ
authors: Lazzara
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003198:Computer Simulation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D018773:Genes, erbB-1; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D004815:Epidermal Growth Factor; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases