Figure 1. Top: pathways of EGFR internalization at low and high EGF concentration. Middle: schematic representation of EGFR ubiquitination, phosphorylation, and endocytic routes as a function of ligand concentration. Bottom: cooperativity mechanism responsible for the EGFR–Ub threshold. Three phosphotyrosines (pY) are critical for the cooperative recruitment of Cbl to active EGFR: pY1045 binds directly to Cbl, pY1068/pY1086 bind indirectly to Cbl:Grb2 complex.