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Open Access Research article

Spatio-temporal modeling of signaling protein recruitment to EGFR

Ming-yu Hsieh1, Shujie Yang2, Mary Ann Raymond-Stinz2, Jeremy S Edwards34* and Bridget S Wilson2

Author Affiliations

1 Department of Electrical and Computer Engineering, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, USA

2 Department of Pathology, University of New Mexico Health Sciences Center, 1 University of New Mexico, Albuquerque, NM 87131, USA

3 Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 1 University of New Mexico, Albuquerque, NM 87131, USA and Chemical and Nuclear Engineering, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, USA

4 The University of New Mexico Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, 1 University of New Mexico, Albuquerque, NM, 87131, USA

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BMC Systems Biology 2010, 4:57  doi:10.1186/1752-0509-4-57

Published: 6 May 2010

Abstract

Background

A stochastic simulator was implemented to study EGFR signal initiation in 3D with single molecule detail. The model considers previously unexplored contributions to receptor-adaptor coupling, such as receptor clustering and diffusive properties of both receptors and binding partners. The agent-based and rule-based approach permits consideration of combinatorial complexity, a problem associated with multiple phosphorylation sites and the potential for simultaneous binding of adaptors.

Results

The model was used to simulate recruitment of four different signaling molecules (Grb2, PLCĪ³1, 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.

Conclusions

Overall, we propose that receptor density, reaction kinetics and membrane spatial organization all contribute to signaling efficiency and influence the carcinogenesis process.