Model for mechanism of feedback inhibition of EGFR by Mig6 (adapted from Park et al., 2015). Activated EGFR upregulates the expression of Mig6 via the Ras-RAF-Map kinase signaling pathway. Mig6 segment 1 binds to dimerization interface of EGFR monomer and block the further asymmetric dimerization. In addition, Src activated by EGFR phosphorylates Mig6 on Y395 in segment 2. This phospho-segment 2 of Mig6 interact with EGFR and is further phosphorylated on Y394, which renders it a potent inhibitor of EGFR. After phosphorylation, segment 2 bound to EGFR rearranges to block the peptide-substrate binding cleft. A single Mig6 protein should be sufficient to inactivate the wildtype receptor, as only one subunit in the asymmetric dimer is active and able to phosphorylate Mig6.
