Mig6 not only inhibits EGFR and HER2 but also targets HER3 and HER4 in a differential specificity: Implications for targeted esophageal cancer therapy

The human EGF receptor family plays pivotal roles in physiology and cancer, which contains four closely related members: HER1/EGFR, HER2, HER3 and HER4. Previously, it was found that the mitogeninducible gene 6 (Mig6) protein is a negative regulator of EGFR and HER2 by using its S1 segment to bind at the kinase dimerization interface. However, it is still unclear whether the S1 segment can also effectively target HER3 and HER4? Here, we performed a systematic investigation to address this issue. The segment can bind to all the four HER kinases with a varying affinity and moderate selectivity; breaking of the segment into shorter hotspot peptides would largely impair the affinity and selectivity, indicating that the full-length sequence is required for the effective binding of S1 to these kinases. The hs2 peptide, which corresponds to the middle hotspot region of S1 segment, can partially retain the affinity to HER kinases, can moderately compete with S1 segment at the dimerization interfaces, and can mimic the biological function of Mig6 protein to suppress HER4 thorn esophageal cancer at cellular level. In addition, we also analyzed the binding potency of S1 segment and hs2 peptide to the kinase domains of other five widely documented growth factor receptors (GFRs). It was showed that both the S1 and hs2 cannot effectively interact with these receptors. Overall, the Mig6 is suggested as a specific pan-HER inhibitor, which can target and suppress HER family members with a broad selectivity, but exhibits weak or no activity towards other GFRs. (c) 2021 Published by Elsevier B.V.

Automated summary

The Mig6 protein is suggested as a specific pan-HER inhibitor, targeting and suppressing HER family members with broad selectivity but weak or no activity towards other growth factor receptors. The S1 segment effectively binds to all four HER kinases, with the full-length sequence being required for effective binding, while the hs2 peptide retains some affinity with HER kinases and mimics the biological function of Mig6 protein in suppressing HER4 at cellular level.