title: Selenoprotein W controls epidermal growth factor receptor surface expression, activation and degradation via receptor ubiquitination.
abstract: Epidermal growth factor (EGF) receptor (EGFR) is the founding member of the ErbB family of growth factor receptors that modulate a complex network of intracellular signaling pathways controlling growth, proliferation, differentiation, and motility. Selenoprotein W (SEPW1) is a highly conserved, diet-regulated 9kDa thioredoxin-like protein required for normal cell cycle progression. We report here that SEPW1 is required for EGF-induced EGFR activation and that it functions by suppressing EGFR ubiquitination and receptor degradation. SEPW1 depletion inhibited EGF-dependent cell cycle entry in breast and prostate epithelial cells. In prostate cells, SEPW1 depletion decreased EGFR auto-phosphorylation, while SEPW1 overexpression increased EGFR auto-phosphorylation. SEPW1 depletion increased the rate of EGFR degradation, which decreased total and surface EGFR and suppressed EGF-dependent EGFR endocytosis, EGFR dimer formation, and activation of EGF-dependent pathways. EGFR ubiquitination was increased in SEPW1-depleted cells--in agreement with the increased rate of EGFR degradation, and suggests that SEPW1 suppresses EGFR ubiquitination. Ubiquitination-directed lysozomal degradation controls post-translational EGFR expression and is dysregulated in many cancers. Thus, suppression of EGFR ubiquitination by SEPW1 may be related to the putative increase in cancer risk associated with high selenium intakes. Knowledge of the mechanisms underlying SEPW1's regulation of EGFR ubiquitination may reveal new opportunities for nutritional cancer prevention or cancer drug development.
authors.affiliation: USDA-ARS Western Human Nutrition Research Center, 430 West Health Sciences Drive, University of California, Davis, CA 95616, USA. Electronic address: zeynep.alkan@ars.usda.gov.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Alkan
authors.affiliation: Cedars Sinai Medical Center, Department of Medicine, 8750 Beverly Boulevard, Atrium 103, West Hollywood, CA 90048, USA.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Duong
authors.affiliation: USDA-ARS Western Human Nutrition Research Center, 430 West Health Sciences Drive, University of California, Davis, CA 95616, USA.
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Hawkes
mesh_terms: D001940:Breast / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011467:Prostate / Q000166:cytology; D055503:Protein Multimerization / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051151:Selenoprotein W / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D051151:Selenoprotein W; D004815:Epidermal Growth Factor; D066246:ErbB Receptors
keywords: Cancer; Epidermal growth factor receptor; Selenium; Selenoprotein W; Ubiquitination