Dose-dependent entry routes for the EGFR. A) At low doses of EGF, EGFR is mainly internalized through clathrin pathway (CME, clathrin-mediated endocytosis). In this condition, ubiquitination of the receptor is not required for its internalization. B) At higher doses of EGF, CME is equally active but a significant part of EGFR internalization proceeds also to an alternative pathway (NCE, non-clathrin endocytosis). The exact nature, and the molecular determinants, of this "alternative" pathway are still controversial. Essentially NCE is defined by its insensitivity to functional ablation (KD) of clathrin and sensitivity to cholesterol-interfering drugs, like filipin. Hence, its definition as a "raft-dependent pathway". Internalization of EGFR through NCE requires receptor ubiquitination. Multiple roles of Eps15/R and epsin in the different internalization pathways are also shown (see main text for detailed explanations).