Spatio-temporal modeling of signaling protein recruitment to EGFR

The model was used to simulate recruitment of four different signaling molecules (Grb2, PLCγ1, Stat5, Shc) to the phosphorylated EGFR tail, with rules based on coarse-grained prediction of spatial constraints. Parameters were derived in part from quantitative immunoblotting, immunoprecipitation and electron microscopy data. Results demonstrate that receptor clustering increases the efficiency of individual adaptor retainment on activated EGFR, an effect that is overridden if crowding is imposed by receptor overexpression. Simultaneous docking of multiple proteins is highly dependent on receptor-adaptor stability and independent of clustering.Overall, we propose that receptor density, reaction kinetics and membrane spatial organization all contribute to signaling efficiency and influence the carcinogenesis process.The ErbB or Epidermal Growth Factor Receptor (EGFR) family of receptor tyrosine kinases consists of four members: EGFR (ErbB1), ErbB2, ErbB3, and ErbB4. Under normal physiological conditions, they propagate signals regulating cell proliferation, differentiation, motility and apoptosis. Changes in expression and aberrant activation, especially of EGFR and ErbB2, are associated with a variety of cancers [1]. Upon ligand binding, EGFR undergoes a conformational change that leads to the formation of homodimers (EGFR-EGFR) and heterodimers (i.e., EGFR-ErbB2) [2]. Dimerization induces kinase activation and transphosphorylation of multiple tyrosine residues in receptor cytoplasmic tails [3-5]. The phosphotyrosine residues serve as docking sites for a large number of cytoplasmic adaptor proteins and enzymes [6]. For a given cell type, the specificity and potency of EGFR-mediated intracellular signaling is mediated by the cell's repertoire of phosphotyrosine-binding proteins recruited to the EGFR cytoplasmic tail.In this work, we use an agent-based model to evaluate the effects of reaction kinetics, steric constraints and receptor clustering on the docking of four E