title: Regulation of EGFR protein stability by the HECT-type ubiquitin ligase SMURF2.
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 that SMURF2-mediated protective ubiquitination of EGFR may be responsible for EGFR overexpression in certain tumors and support targeting SMURF2-EGFR interaction as a novel therapeutic approach in treating EGFR-addicted tumors.
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA. dipray@umich.edu
authors.forename: Dipankar
authors.initials: D
authors.lastname: Ray
authors.forename: Aarif
authors.initials: A
authors.lastname: Ahsan
authors.forename: Abigail
authors.initials: A
authors.lastname: Helman
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.forename: Ashok
authors.initials: A
authors.lastname: Hegde
authors.forename: Susmita Ramanand
authors.initials: SR
authors.lastname: Gurjar
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kiyokawa
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Nyati
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; C512478:EGFR protein, human; D066246:ErbB Receptors