Proposed model of dimerization requirements for receptor activation by wildtype EGFR and oncogenic mutants (adapted from Cho et al., 2013). (A) Activation of wildtype EGFR is initiated by ligand-induced extracellular dimerization of the receptor, which in turn direct “outside-in” asymmetric dimerization of the N- and C-lobes in the kinase domain, leading to enzymatic activation of the receiver monomer and subsequent autophosphorylation on the C-terminal tail of the activator monomer. Therefore, full enzymatic activation and consequent signaling cascade of the wildtype EGFR are tightly dependent on all sequential events of ligand binding, dimerization and autophosphorylation. (B) A group of EGFR mutants including the L858R, most colon cancer-derived and C-terminal truncation EGFR mutants are able to form constitutive asymmetric dimerization irrespective of ligand binding, which in turn promotes “inside-out” extracellular dimerization; ligand increases dimerization but is not required. Interruption of dimerization impairs the oncogenic activity of these types of mutant EGFR because the receiver monomer is no longer active. Thus, mutant EGFR belong to this group is sensitive to EGFR-directed mAs such as cetuximab. (C) In contrast, a subset of mutant EGFR including the Ex19Del and Ex20Ins mutants and the L858R/T790M double mutants similarly undergo dimerization in the absence of ligand, but do not require dimerization for their activity. These mutant forms of EGFR acquire the oncogenic activity in dimerization-independent manner so that these mutants are refractory to EGFR mAbs.
