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 mitogen-inducible 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+ 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.

人类 EGF 受体家族在生理和癌症中起关键作用，其中包含四个密切相关的成员：HER1/EGFR、HER2、HER3 和 HER4。此前，人们发现丝裂原诱导基因 6 (Mig6) 蛋白是 EGFR 和 HER2 的负调节因子，通过其 S1 片段与激酶二聚化界面结合。不过，目前还不清楚S1段是否也能有效靶向HER3和HER4？在这里，我们进行了系统的调查来解决这个问题。该片段可以以不同的亲和力和适度的选择性与所有四种 HER 激酶结合；将片段分解成更短的热点肽会在很大程度上损害亲和力和选择性，这表明 S1 与这些激酶的有效结合需要全长序列。HS _2肽对应于S1片段的中间热点区域，可部分保留对HER激酶的亲和力，在二聚化界面与S1片段适度竞争，可模拟Mig6蛋白在细胞上抑制HER4+食管癌的生物学功能等级。此外，我们还分析了 S1 片段和hs 2 肽与其他五种广泛记录的生长因子受体 (GFR) 的激酶结构域的结合效力。结果表明，S1 和hs 2 都不能有效地与这些受体相互作用。总体而言，Mig6 被认为是一种特异性泛 HER 抑制剂，它可以广泛选择性地靶向和抑制 HER 家族成员，但对其他 GFR 表现出较弱或没有活性。