Key References for

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Cho J., BMB Rep 53(3)

Park E.....Cho J.

Nat Struct  Mol Biol. 22(9)


 항암 분자표적치료제

내성 유발 돌연변이 제어 기초 연구실



    Mitogen-inducible gene 6 (Mig6), also known as RALT, is a negative feedback inhibitor of EGFR and other ErbB family members. Mig6 expression is transcriptionally induced by hormones, growth factors, and various stress stimuli via the Ras-Raf-ERK signaling pathway. By complexing with EGFR mediating revolutionary conserved domains (segment 1 and 2), Mig6 effectively inhibits EGFR activation and its downstream signaling pathways via three proposed mechanisms in an orchestrated manner. First, Mig6 binds to the C-lobe of the active EGFR kinase domain through segment 1 and blocks the asymmetric dimer formation with the N-lobe of the other EGFR monomer, required for full enzymatic activation of EGFR as described above. Second, phosphorylated Mig6 at segment 2 binds strongly to the EGFR kinase domain and directly suppresses its catalytic activity in a peptide substrate competitive manner. In addition, Mig6 can complex with EGFR and induce its internalization and degradation. Such coordinated actions seem to render Mig6 as a tight negative regulator of EGFR and its signaling circuits to prevent aberrant EGFR activation leading to cellular transformation. Consistent with this notion, the loss of Errfi1 (ERBB receptor feedback inhibitor 1, official gene name of Mig6) in mice was shown to induce a high incidence of neoplastic lesions caused by abnormal activation of EGFR signaling. Furthermore, frequent focal deletions of ERRFI1 were identified from the analysis of 1,057 gliomas supporting the fact that the loss of Mig6 is a key driving force of human cancer.

    The breakthrough findings of the key molecular mechanism underlying Mig6-mediated negative feedback regulation of EGFR was conducted through X-ray crystal-based structural studies followed by elaborate biochemical characterization. These studies revealed that Mig6 strongly interacts with EGFR in the asymmetric dimerization interface of EGFR kinase domain C-lobe and N-lobe regions. Also, this interaction is mediated by a specific domain of Mig6 known as segment 1 (S1), one of two evolutionary conserved regions within Mig6. Given that EGFR asymmetric dimerization is required for full enzymatic activation of EGFR, the binding of Mig6 S1 to EGFR abrogates the formation of intact dimerization of EGFR and consequently blocks its activation. Mig6 also appears to prevent asymmetric dimerization among the other ErbB family members via the same interacting mechanism. Thus, the preclusion of asymmetric dimerization by Mig6 S1 is a key negative regulatory mechanism among ErbB members.


    One puzzling observation not clearly addressed in the original structural analysis was the functional significance of the other interaction of Mig6 at the substrate binding site of EGFR, mediated by Mig6 segment 2 (S2) (45). Recent additional crystal structural, biochemical and functional studies demonstrated the role of Mig6 S2-mediated interaction in inhibiting EGFR activation and identified the detailed molecular mechanism of how Mig6 S2 contributes to this process (4653). According to these findings, Mig6 remains an incomplete inhibitor of EGFR until a series of posttranslational modifications occurs in segment 2; Mig6 undergoes tyrosine phosphorylation at 395 in S2 region by Src, which in turn becomes a suitable substrate of EGFR (46). Next, additional phosphorylation is induced by EGFR in Mig6 at tyrosine 394, which dramatically increases the binding affinity of Mig6 to the EGFR active site and consequently, Mig6 becomes a potential competitive inhibitor blocking other substrate access to EGFR (Fig. 3) (46). The functional significance of these events was further validated using in vitro models. While phosphorylation-competent Mig6 effectively prevents EGFR mutants from causing oncogenic transformations, this was not the case with Mig6 Y394F/Y395F mutants under the same experimental conditions (46).

    In conclusion, Mig6 negatively regulates EGFR and its signaling pathways through several distinct mechanisms; blockage of EGFR asymmetric dimerization by the S1 region and potential competitive inhibition of substrate access by the phosphorylated S2 region. This signaling circuit-based regulatory mechanism renders Mig6 effective in selectively targeting active EGFR.

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.

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