BIOPHYSICAL THEORY AND MODELING |
Modeling the effects of HER/ErbB1-3 co-expression on receptor dimerization and biological response
Harish Shankaran 1, H. Steven Wiley 1 and Haluk Resat 1*
1 Pacific Northwest National Laboratory
* To whom correspondence should be addressed. E-mail: haluk.resat{at}pnl.gov.
Submitted on December 29, 2005
Revised on February 2, 2006
Accepted on 28 February 2006
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Abstract |
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The human epidermal growth factor receptor (HER/ErbB) system comprises the epidermal growth factor receptor (EGFR/HER1) and three other homologues viz. HER2-4. This receptor system plays a critical role in cell proliferation and differentiation and receptor over-expression has been associated with poor prognosis in cancers of the epithelium. Here, we examine the effect of co-expressing varying levels of HER1-3 on the receptor dimerization patterns using a detailed kinetic model for HER/ErbB dimerization and trafficking. Our results indicate that co-expression of EGFR with HER2 or HER3 biases signaling to the cell surface and retards signal down-regulation. In addition, simultaneous co-expression of HER1-3 leads to an abundance of HER2-HER3 heterodimers, which are known to be potent inducers of cell growth and transformation. Our new approach to use parameter dependence analysis in experimental design reveals that measurements of HER3 phosphorylation and HER2 internalization ratio may prove to be especially useful for the estimation of critical model parameters. Further, we examine the effect of receptor dimerization patterns on biological response using a simple phenomenological model. Results indicate that co-expression of EGFR with HER2 and HER3 at low to moderate levels may enable cells to match the response of a high HER2 expresser.
Key Words:
EGFR/HER/ErbB, biological networks, endocytosis, mathematical modeling, sensitivity analysis, signal transduction
