Abstract
Graphical Abstract Highlights d Distinct classes of CCPs exist, molecularly defined by the presence or lack of AP2 d The AP2-negative CCPs support the internalization of EGFR but not of TfR d The AP2-negative CCPs rely on the endocytic adaptors eps15/eps15L1 and epsin1 d The two classes of CCPs determine distinct EGFR fates and signaling outputs In Brief EGFR signaling controls different cell physiological processes, including proliferation and migration. Pascolutti et al. describe an additional layer of regulation of EGFR signaling, relying on the sequestration of receptors into molecularly distinct clathrin-coated vesicles that regulate receptor fate toward recycling versus degradation, with impact on the final cellular output.