Regulation of EGFR Protein Stability by the HECT-type Ubiquitin Ligase SMURF2

摘要: Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial tumors and considered to be an important therapeutic target. Although gene amplification responsible for EGFR overexpression certain human malignancies including lung head neck cancers, additional molecular mechanisms are likely. Here, we report novel interaction with HECT-type ubiquitin ligase SMURF2, which can ubiquitinate, but stabilize by protecting it from c-Cbl-mediated degradation. Conversely, small interfering RNA (siRNA)-mediated knockdown SMURF2 destabilized EGFR, induced autophagic response reduced the clonogenic survival EGFR-expressing cancer cell lines, minimal effects on EGFR-negative cells, normal fibroblasts, cells. UMSCC74B squamous form aggressive nudemice, significantly lost vivo tumor-forming ability siRNA-mediated knockdown. Gene expressionmicroarray data 443 adenocarcinoma patients, tissue microarray 67 such showed strong correlation expression between at messenger protein levels, respectively. Our findings suggest that SMURF2-mediated protective ubiquitination may support targeting SMURF2-EGFR as approach treating EGFR-addicted tumors.