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| Subject Categories: Signal Transduction |
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| The EMBO Journal
(2006) 25, 5683–5692, doi:10.1038/sj.emboj.7601457 Published online 30 November 2006 |
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| p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration |
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| Mark R Frey1, Rebecca S Dise2, Karen L Edelblum2 and D Brent Polk1, 2 |
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1 Division of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA 2 Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA To whom correspondence should be addressed D Brent Polk, Division of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, MRB IV Room 1025, 2215 Garland Avenue, Nashville, TN 37232-0696, USA. Tel.: +1 615 322 7449; Fax: +1 615 343 5323; E-mail: d-brent.polk@vanderbilt.edu Received 8 May 2006; Accepted 27 October 2006; Published online 30 November 2006. |
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| Abstract |
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| Internalization and proteolytic degradation of epidermal growth factor (EGF) receptor (R) following ligand binding is an important mechanism for regulating EGF-stimulated signals. Using pharmacological and RNA interference inhibition of p38 mitogen-activated protein kinase, we show that p38 is required for efficient EGF-induced EGFR destruction but not internalization. In the absence of p38 activity, EGF fails to stimulate the ubiquitin ligase Cbl or ubiquitinylation of EGFR, and internalized EGFR accumulates in intracellular vesicles containing caveolin-1. These effects are accompanied by loss of EGFR phosphorylation on Y1045, a phosphorylation site required for Cbl activation. Furthermore, similar to cells treated with p38 inhibitors, intestinal epithelial cells expressing Y1045F EGFR mutants show increased proliferation but not migration in response to EGF, thus uncoupling these biological responses. Together these data position p38 as a modulator of ligand-stimulated EGFR processing and demonstrate that this processing has a profound impact on the cellular outcome of EGFR signaling. |
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| Keywords: EGF receptor, intestinal epithelium, p38 MAPK, ubiquitinylation, wound healing |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHp38 kinase regulates epidermal growth factor receptor downregulation and cellular migration The EMBO Journal Article p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy The EMBO Journal Article p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy The EMBO Journal Article (20 Sep 2006) The EMBO Journal Article (16 Sep 2002) |
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