EGFR ubiquitination by Cbl. Upon EGF-dependent receptor activation, the GRB2-Cbl complex binds to the receptor through interactions of: i) the SH2 domain of GRB2 with pY1045 of EGFR, and ii) the TKB domain of Cbl (either c-Cbl or Cbl-b) with pY1068 or pY1086. This substrate interaction may either stabilize or select for a partially open Cbl conformation (see bottom panel and main text). EGFR-bound Cbl becomes phosphorylated on a critical tyrosine, leading to full rotation of the linker region. This, in turn, exposes the RING domain for ubiquitin-charged E2 binding, resulting in the allosteric activation of the E2 by Cbl and ubiquitination of the EGFR. Note that, to simplify the picture, Cbl bound to one receptor molecule is depicted to ubiquitinate the other molecule of the dimer. No available data suggest that this is indeed the case. For simplicity, the EGF receptor is depicted as monoubiquitinated: in reality, it is both multimono- and polyubiquitinated.