The signaling and transformation potency of the overexpressed HER2 protein is dependent on the normally-expressed EGFR

► HER2 confers EGFR resistance to ligand-induced degradation by channeling to recycling endosomes. ► Enhanced receptor recycling induced by HER2 leads to biphasic signaling pattern. ► HER2 overexpression-induced optimal signaling and transformation is dependent on EGFR. ► Therefore, the oncogenic property of HER2 is dependent on the normally-expressed EGFR.