Activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) leads to the constitutively active kinase, improves the EGFR stability and promotes malignant transformation in lung adenocarcinoma. Despite the clinical significance, the mechanism by which the increased kinase activity stabilizes the receptor is not completely understood. Using SILAC phosphoproteomic approach, we identify that Mig6 is highly phosphorylated at S256 in EGFR mutants (19del and L858R). Loss of Mig6 contributes to the efficient degradation of EGFR wildtype and mutants in lung cancer cells. Mig6 regulates the recruitment of c-Cbl to EGFR as the ablation of Mig6 enables efficient ubiquitination of the EGFR mutants through elevated recruitment of c-Cbl. We show that the cells with activating mutants of EGFR inactivate Mig6 through phosphorylation at S256. Inactivated Mig6 causes inefficient ubiquitination of EGFR, leading to defective degradation of the receptor thus contributing to the increased stability of the receptor. Taken together, we show a novel function of Mig6 in regulating the ubiquitination of EGFR.

表皮生长因子受体（EGFR）激酶结构域中的激活突变导致组成性活性激酶，提高EGFR稳定性并促进肺腺癌的恶性转化。尽管具有临床意义，但是增强激酶活性使受体稳定的机理尚不完全清楚。使用SILAC磷酸化蛋白质组学方法，我们确定Mig6在EGFR突变体（19del和L858R）的S256处高度磷酸化。Mig6的丢失有助于肺癌细胞中EGFR野生型和突变体的有效降解。Mig6调节c-Cbl向EGFR的募集，因为Mig6的消融能够通过提高c-Cbl的募集来使EGFR突变体有效泛素化。我们显示具有EGFR激活突变体的细胞通过在S256处的磷酸化使Mig6失活。灭活的Mig6导致EGFR的泛素化效率低下，导致受体的降解降解，从而导致受体稳定性提高。综上所述，我们显示了Mig6在调节EGFR泛素化中的新功能。