表皮生长因子受体（EGFR）失调是与各种癌症发病机制相关的最常见机制之一。有丝分裂原诱导基因 6 [MIG6；也称为 ERBB 受体反馈抑制剂 1 (ERRFI1)]，被确定为 EGFR 的反馈抑制剂，通过直接抑制 EGFR 激酶活性并促进其内化，从而负向调节 EGFR，随后导致降解。尽管其被提议作为 EGFR 依赖性肿瘤抑制因子，但其在癌症病因学中的功能后果和临床相关性仍不完全清楚。在这里，我们发现 MIG6 和 EGFR 之间的化学计量平衡对于促进各种实验模型系统中 EGFR 依赖性致癌生长至关重要。此外，ERRFI1（MIG6 的官方基因符号）突变的一个子集表现出在多个水平上抑制 EGFR 酶促激活的能力受损。总之，我们的数据表明 MIG6 活性降低或丧失可能导致 EGFR 异常激活，可能导致细胞转化。我们建议 ERRFI1 的突变状态和 MIG6 的表达水平可以作为指导 EGFR 靶向癌症治疗（包括胶质母细胞瘤）的额外生物标志物。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Dysregulation of epidermal growth factor receptor (EGFR) is one of the most common mechanisms associated with the pathogenesis of various cancers. Mitogen-inducible gene 6 [MIG6; also known as ERBB receptor feedback inhibitor 1 (ERRFI1)], identified as a feedback inhibitor of EGFR, negatively regulates EGFR by directly inhibiting its kinase activity and facilitating its internalization, subsequently leading to degradation. Despite its proposed role as an EGFR-dependent tumor suppressor, the functional consequences and clinical relevance in cancer etiology remain incompletely understood. Here, we identify that the stoichiometric balance between MIG6 and EGFR is crucial in promoting EGFR-dependent oncogenic growth in various experimental model systems. In addition, a subset of ERRFI1 (the official gene symbol of MIG6) mutations exhibit impaired ability to suppress the enzymatic activation of EGFR at multiple levels. In summary, our data suggest that decreased or loss of MIG6 activity can lead to abnormal activation of EGFR, potentially contributing to cellular transformation. We propose that the mutation status of ERRFI1 and the expression levels of MIG6 can serve as additional biomarkers for guiding EGFR-targeted cancer therapies, including glioblastoma.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.