Jul 14, 2011

Regulation of EGFR protein stability by the HECT-type ubiquitin ligase SMURF2

Neoplasia : an International Journal for Oncology Research
Dipankar RayMukesh K Nyati

Abstract

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

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Mentioned in this Paper

Cricetulus
SMURF2 gene
EGFR
Adenocarcinoma of Lung (Disorder)
Gene Expression Regulation, Neoplastic
Xenograft Model Antitumor Assays
Egfr
Specimen Type - Fibroblasts
Gene Amplification
Lung

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