Ubiquitination of adaptors. (a) Agonist induces rapid ubiquitination of GPCR-recruited ARR by MDM2, a process required for receptor internalization. Once internalized, GPCRs can be dephosphorylated and rapidly recycled to the plasma membrane through a mechanism that involves the sorting proteins EBP50 and NSF. (b) Activated EGFR is ubiquitinated at the plasma membrane by Cbl and recruits the UBD-containing endocytic adaptors EPS15 and EPSIN-1 at the plasma membrane, and subsequently HRS at the endosomal membrane. These adaptors, in turn, are ubiquitinated by NEDD4 through a process known as coupled monoubiquitination. This directs progression of the ubiquitinated receptors toward lysosomal degradation through the ESCRT complexes. A similar mechanism can be envisioned for other RTKs.