Weak binding to E3 ubiquitin ligase c-Cbl increases EGFRvA protein stability

Recently, we have identified a novel epidermal growth factor receptor isoform (EGFRvA), which has higher tumor-promoting capacity than EGFR. However, the underlying mechanism is not well understood. Here, we demonstrate that EGFRvA is more stable than EGFR. Interestingly, we observe that EGFRvA binds less to E3 ubiquitin ligase c-Cbl than EGFR does, although Y1045, a direct binding site of c-Cbl, is well phosphorylated in both of them. Further study reveals that EGFRvA cannot bind to Grb2, an important binding mediator between EGFR and c-Cbl. Thus, our study finds that EGFRvA is more stable than EGFR because of its decreased binding to c-Cbl.