Regulation of EGFR protein stability by the HECT-type ubiquitin ligase smurf21,2

Dipankar Ray*, Aarif Ahsan, Abigail Helman, Guoan Chen, Ashok Hegde, Susmita Ramanand Gurjar, Lili Zhao, Hiroaki Kiyokawa, David G. Beer, Theodore S. Lawrence, Mukesh K. Nyati

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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 EGFRexpressing 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 nudemice, significantly lost in vivo tumor-forming ability on siRNA-mediated SMURF2 knockdown. Gene expressionmicroarray 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 thatSMURF2-mediated protective ubiquitination of EGFRmay be responsible for EGFR overexpression in certain tumors and support targeting SMURF2-EGFR interaction as a novel therapeutic approach in treating EGFR-addicted tumors.

Original languageEnglish (US)
Pages (from-to)570-578
Number of pages9
JournalNeoplasia
Volume13
Issue number7
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Cancer Research

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