TY - JOUR
T1 - Regulation of EGFR protein stability by the HECT-type ubiquitin ligase smurf21,2
AU - Ray, Dipankar
AU - Ahsan, Aarif
AU - Helman, Abigail
AU - Chen, Guoan
AU - Hegde, Ashok
AU - Gurjar, Susmita Ramanand
AU - Zhao, Lili
AU - Kiyokawa, Hiroaki
AU - Beer, David G.
AU - Lawrence, Theodore S.
AU - Nyati, Mukesh K.
N1 - Funding Information:
Address all correspondence to: Dipankar Ray, PhD, Department of Radiation Oncology, University of Michigan, 1301 Catherine St, Med Sci I, Rm. 4326A, Ann Arbor, MI 48109. E-mail: dipray@umich.edu 1This work was supported by grants R01CA131290 and P50 CADE97248 (to M.K.N.) and University of Michigan Cancer Center support grant 5 P30 CA46592. 2This article refers to supplementary material, which is designated by Figure W1 and is available online at www.neoplasia.com. 3These authors contributed equally. Received 5 May 2011; Revised 17 May 2011; Accepted 18 May 2011 Copyright © 2011 Neoplasia Press, Inc. All rights reserved 1522-8002/11/$25.00 DOI 10.1593/neo.11632
PY - 2011/7
Y1 - 2011/7
N2 - 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.
AB - 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.
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U2 - 10.1593/neo.11632
DO - 10.1593/neo.11632
M3 - Article
C2 - 21750651
AN - SCOPUS:79960060557
SN - 1522-8002
VL - 13
SP - 570
EP - 578
JO - Neoplasia
JF - Neoplasia
IS - 7
ER -