Phosphorylation of Mig6 negatively regulates the ubiquitination and degradation of EGFR mutants in lung adenocarcinoma cell lines.

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.