Abstract
Endocytic trafficking plays an important role in the regulation of the epidermal growth factor receptor (EGFR) family. Many cell types express multiple EGFR family members (including EGFR, HER2, HER3, and/or HER4) that interact to form an array of homo- and heterodimers. Differential trafficking of these receptors should strongly affect signaling through this system by changing substrate access and heterodimerization efficiency. Because of the complexity of these dynamic processes, we used a quantitative and computational model to understand their integrated operation. Parameters characterizing EGFR and HER2 interactions were determined using experimental data obtained from mammary epithelial cells constructed to express different levels of HER2, enabling us to estimate receptor-specific internalization rate constants and dimer uncoupling rate constants. Significant novel results obtained from this work are as follows: first, that EGFR homodimerization and EGFR/HER2 heterodimerization occur with comparable affinities; second, that EGFR/HER2 heterodimers traffic as single entities. Furthermore, model predictions of the relationship of HER2 expression levels to consequent distribution of EGFR homodimers and EGFR/HER2 heterodimers suggest that the levels of HER2 found on normal cells are barely at the threshold necessary to drive efficient heterodimerization. Thus, altering HER2 concentrations, either overall or local, could provide an effective mechanism for regulating EGFR/HER2 heterodimerization and may explain why HER2 overexpression found in some cancers has such a profound effect on cell physiology.
Highlights
Endocytic trafficking plays an important role in the regulation of the epidermal growth factor receptor (EGFR) family
We found the following: (i) EGFR/HER2 heterodimers are internalized as single entities, with other models of internalization being inconsistent with literature data [25]; (ii) EGFR/HER2 heterodimers have a comparable dimerization affinity as EGFR/EGFR homodimers, the notion of HER2 as a preferred dimerization partner should be re-assessed; and (iii) there appears to be a threshold level of HER2 above which heterodimerization is maximal but increased HER2 expression is still able to alter signaling through longer term effects
We explored the importance of heterodimerization in the internalization of both EGFR and HER2 as a function of HER2 expression level using previously published experimental data and a computational model of EGFR and HER2 internalization
Summary
Endocytic trafficking plays an important role in the regulation of the epidermal growth factor receptor (EGFR) family. Many cell types express multiple EGFR family members (including EGFR, HER2, HER3, and/or HER4) that interact to form an array of homo- and heterodimers. Differential trafficking of these receptors should strongly affect signaling through this system by changing substrate access and heterodimerization efficiency. HER2 behaves much like a receptor subunit, as it binds none of the eight reported EGF family ligands (EGF, transforming growth factor-␣, betacellulin, amphiregulin, heparinbinding EGF, epiregulin, and the neuregulins (NRG and NRG2)) with high affinity [5] Overexpression of both the EGFR and HER2 has been associated with cell transformation and tumorigenesis. Increased HER2 expression contributes to cell transformation, anchorage-independent cell growth, increased proliferation and mitogenic sensitivity, as well as increased tumor cell migration and invasiveness (8 –11)
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