title: HER2-mediated effects on EGFR endosomal sorting: analysis of biophysical mechanisms.
abstract: Overexpression of HER2, a receptor-like tyrosine kinase and signaling partner for the epidermal growth factor receptor (EGFR), has been implicated in numerous experimental and clinical studies as promoting the progression of many types of cancer. One avenue by which HER2 overexpression may dysregulate EGFR-mediated cell responses, such as proliferation and migration, downstream of EGF family ligand binding, is by its modulation on EGFR endocytic trafficking dynamics. EGFR signaling is regulated by downregulation and compartmental relocalization arising from endocytic internalization and endosomal sorting to degradation versus recycling fates. HER2 overexpression influences both of these processes. At the endosomal sorting stage, increased HER2 levels elicit enhanced EGFR recycling outcomes, but the mechanism by which this transpires is poorly understood. Here, we determine whether alternative mechanisms for HER2-mediated enhancement of EGFR recycling can be distinguished by comparison of corresponding mathematical models to experimental literature data. Indeed, we find that the experimental data are clearly most consistent with a mechanism in which HER2 directly competes with EGFR for a stoichiometrically-limited quantity of endosomal retention components (ERCs), thereby reducing degradation of ERC-coupled EGFR. Model predictions based on this mechanism exhibited qualitative trends highly similar to data on the fraction of EGF/EGFR complexes sorted to recycling fate as a function of the amount of internalized EGF/EGFR complexes. In contrast, model predictions for alternative mechanisms-blocking of EGFR/ERC coupling, or altering EGF/EGFR dissociation-were inconsistent with the qualitative trends of the experimental data.
mesh_terms: D003198:Computer Simulation; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000502:physiology*; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D021381:Protein Transport / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases