{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T15:17:59Z","timestamp":1778253479050,"version":"3.51.4"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,2,4]],"date-time":"2020-02-04T00:00:00Z","timestamp":1580774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["16K07058"],"award-info":[{"award-number":["16K07058"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["17K07112"],"award-info":[{"award-number":["17K07112"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Accumulating evidences suggested that the overactivation of epidermal growth factor receptor (EGFR) was involved in the development of adult respiratory distress syndrome and pulmonary fibrosis. Elucidation of the mechanisms that regulate EGFR residence on the plasma membrane during inflammatory lung conditions is important for identifying potential therapies. We have demonstrated that flagellin phosphorylated EGFR at Ser1047 and induced transient EGFR internalization. In this study, we examined the molecular pathway and effect of interleukin 1 beta (IL-1\u03b2) on EGFR in alveolar epithelial cells. Treatment of A549 cells with IL-1\u03b2 induced the activation of p38 mitogen-activated protein kinase (MAP kinase) and MAP kinase-activated protein kinase-2 (MAPKAPK-2), as well as EGFR phosphorylation at serine 1047. Both MAPKAPK-2 activation and EGFR phosphorylation were inhibited by SB203580, a p38 MAP kinase inhibitor. In addition, MK2a inhibitor (a MAPKAPK-2 inhibitor) suppressed EGFR phosphorylation. Assessment of the biotinylation of cell surface proteins indicated that IL-1\u03b2 induced EGFR internalization. Furthermore, long-term treatment of A549 cells with IL-1\u03b2 caused morphological changes and loss of cell\u2013cell contact. Moreover, IL-1\u03b2 augmented the effect of transforming growth factor beta 1 on the epithelial\u2013mesenchymal transition. These results suggested that IL-1\u03b2 regulates EGFR functions and induces morphological changes of alveolar epithelial cells.<\/jats:p>","DOI":"10.1093\/jb\/mvaa015","type":"journal-article","created":{"date-parts":[[2020,1,25]],"date-time":"2020-01-25T12:11:36Z","timestamp":1579954296000},"page":"113-123","source":"Crossref","is-referenced-by-count":7,"title":["Regulation of epidermal growth factor receptor expression and morphology of lung epithelial cells by interleukin-1\u03b2"],"prefix":"10.1093","volume":"168","author":[{"given":"Izumi","family":"Nakayama","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan"},{"name":"Intensive Care Unit, Department of Internal Medicine, Okinawa Chubu Hospital, Okinawa 904-2293, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayomi","family":"Higa-Nakamine","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Uehara","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Sugahara","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manabu","family":"Kakinohana","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyuki","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,2,4]]},"reference":[{"key":"2020072821265814600_mvaa015-B1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/S0014-4827(02)00100-3","article-title":"ErbB-4: mechanism of action and biology","volume":"284","author":"Carpenter","year":"2003","journal-title":"Exp. Cell Res"},{"key":"2020072821265814600_mvaa015-B2","doi-asserted-by":"crossref","first-page":"5529","DOI":"10.1128\/MCB.00375-09","article-title":"TAK1-mediated serine\/threonine phosphorylation of epidermal growth factor receptor via p38\/extracellular signal-regulated kinase: NF-\u03baB-independent survival pathways in tumor necrosis factor alpha signaling","volume":"29","author":"Nishimura","year":"2009","journal-title":"Mol. Cell Biol."},{"key":"2020072821265814600_mvaa015-B3","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1254\/jphs.13R11CP","article-title":"Desensitization by different strategies of epidermal growth factor receptor and ErbB4","volume":"124","author":"Yamamoto","year":"2014","journal-title":"J. Pharmacol. Sci."},{"key":"2020072821265814600_mvaa015-B4","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S0014-4827(03)00002-8","article-title":"Trafficking of the ErbB receptors and its influence on signaling","volume":"284","author":"Wiley","year":"2003","journal-title":"Exp. Cell Res"},{"key":"2020072821265814600_mvaa015-B5","doi-asserted-by":"crossref","first-page":"34530","DOI":"10.1074\/jbc.M405703200","article-title":"Epidermal growth factor receptor transactivation mediates tumor necrosis factor-induced hepatocyte replication","volume":"279","author":"Argast","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2020072821265814600_mvaa015-B6","doi-asserted-by":"crossref","first-page":"12698","DOI":"10.1074\/jbc.M608723200","article-title":"Transient suppression of ligand-mediated activation of epidermal growth factor receptor by tumor necrosis factor-\u03b1 through the TAK1-p38 signaling pathway","volume":"282","author":"Singhirunnusorn","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2020072821265814600_mvaa015-B7","doi-asserted-by":"crossref","first-page":"4195","DOI":"10.1038\/sj.emboj.7601297","article-title":"p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy","volume":"25","author":"Zwang","year":"2006","journal-title":"EMBO J"},{"key":"2020072821265814600_mvaa015-B8","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.cell.2014.12.006","article-title":"A kinase-independent role for EGF receptor in autophagy initiation","volume":"160","author":"Tan","year":"2015","journal-title":"Cell"},{"key":"2020072821265814600_mvaa015-B9","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.tcb.2015.12.006","article-title":"Stress-induced EGFR trafficking: mechanisms, functions, and therapeutic implications","volume":"26","author":"Tan","year":"2016","journal-title":"Trends. Cell. Biol"},{"key":"2020072821265814600_mvaa015-B10","doi-asserted-by":"crossref","first-page":"L407","DOI":"10.1152\/ajplung.00471.2005","article-title":"Neutrophil elastase induces IL-8 gene transcription and protein release through p38\/NF-\u03baB activation via EGFR transactivation in a lung epithelial cell line","volume":"291","author":"Kuwahara","year":"2006","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol"},{"key":"2020072821265814600_mvaa015-B11","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.pupt.2010.03.002","article-title":"Inhibition by ethyl pyruvate of the nuclear translocation of nuclear factor-\u03baB in cultured lung epithelial cells","volume":"23","author":"Mizutani","year":"2010","journal-title":"Pulm. Pharmacol. Ther"},{"key":"2020072821265814600_mvaa015-B12","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/35074106","article-title":"The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5","volume":"410","author":"Hayashi","year":"2001","journal-title":"Nature"},{"key":"2020072821265814600_mvaa015-B13","doi-asserted-by":"crossref","first-page":"L1057","DOI":"10.1152\/ajplung.00096.2012","article-title":"Induction of epithelial-mesenchymal transition by flagellin in cultured lung epithelial cells","volume":"303","author":"Kondo","year":"2012","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol"},{"key":"2020072821265814600_mvaa015-B14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.abb.2012.11.006","article-title":"Phosphorylation of epidermal growth factor receptor at serine 1047 by MAP kinase-activated protein kinase-2 in cultured lung epithelial cells treated with flagellin","volume":"529","author":"Noguchi","year":"2013","journal-title":"Arch. Biochem. Biophys"},{"key":"2020072821265814600_mvaa015-B15","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ejphar.2014.12.016","article-title":"Differential regulation of epidermal growth factor receptor by hydrogen peroxide and flagellin in cultured lung alveolar epithelial cells","volume":"748","author":"Nishi","year":"2015","journal-title":"Eur. J. Pharmacol"},{"key":"2020072821265814600_mvaa015-B16","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1002\/eji.201141550","article-title":"A clinical perspective of IL-1\u03b2 as the gatekeeper of inflammation","volume":"41","author":"Dinarello","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"2020072821265814600_mvaa015-B17","first-page":"re3","article-title":"The interleukin-1 receptor\/Toll-like receptor superfamily: signal transduction during inflammation and host defense","volume":"171","author":"Dunne","year":"2003","journal-title":"Sci. STKE"},{"key":"2020072821265814600_mvaa015-B18","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of 24 bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"2020072821265814600_mvaa015-B19","doi-asserted-by":"crossref","first-page":"4350","DOI":"10.1073\/pnas.76.9.4350","article-title":"Electrophoretic transfer of proteins from poly-acrylamide gels to nitrocellulose sheets: procedure and some applications","volume":"76","author":"Towbin","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2020072821265814600_mvaa015-B20","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1002\/jcp.22988","article-title":"Selective cleavage of ErbB4 by G-protein-coupled gonadotropin-releasing hormone receptor in cultured hypothalamic neurons","volume":"227","author":"Higa-Nakamine","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"2020072821265814600_mvaa015-B21","doi-asserted-by":"crossref","first-page":"5920","DOI":"10.1002\/j.1460-2075.1995.tb00280.x","article-title":"Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2","volume":"14","author":"Ben-Levy","year":"1995","journal-title":"EMBO J"},{"key":"2020072821265814600_mvaa015-B22","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1002\/jcp.22448","article-title":"Role of Smad2\/3 and p38 MAP kinase in TGF-\u03b21-induced epithelial-mesenchymal transition of pulmonary epithelial cells","volume":"226","author":"Kolosova","year":"2011","journal-title":"J. Cell. Physiol."},{"key":"2020072821265814600_mvaa015-B23","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/nrc2088","article-title":"Epidermal growth factor receptor mutations in lung cancer","volume":"7","author":"Sharma","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"2020072821265814600_mvaa015-B24","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.18632\/oncotarget.1711","article-title":"EGFR endocytosis is a novel therapeutic target in lung cancer with wild-type EGFR","volume":"5","author":"Jo","year":"2014","journal-title":"Oncotarget"},{"key":"2020072821265814600_mvaa015-B25","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1165\/rcmb.2012-0100TR","article-title":"Human epidermal growth factor receptor signaling in acute lung injury","volume":"47","author":"Finigan","year":"2012","journal-title":"Am. J. Respir. Cell Mol. Biol"},{"key":"2020072821265814600_mvaa015-B26","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.1111\/j.1440-1843.2006.00804.x","article-title":"Alveolar epithelial cells: differentiation and lung injury","volume":"11","author":"Sugahara","year":"2006","journal-title":"Respirology"},{"key":"2020072821265814600_mvaa015-B27","doi-asserted-by":"crossref","first-page":"6967","DOI":"10.1073\/pnas.91.15.6967","article-title":"A kinase-negative epidermal growth factor receptor that retains the capacity to stimulate DNA synthesis","volume":"91","author":"Coker","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2020072821265814600_mvaa015-B28","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.ccr.2008.03.015","article-title":"Survival of cancer cells is maintained by EGFR independent of its kinase activity","volume":"13","author":"Weihua","year":"2008","journal-title":"Cancer Cell"},{"key":"2020072821265814600_mvaa015-B29","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.pupt.2017.09.002","article-title":"Phosphorylation of epidermal growth factor receptor at serine 1047 in cultured lung alveolar epithelial cells by bradykinin B2 receptor stimulation","volume":"48","author":"Izumi","year":"2018","journal-title":"Pulm. Pharmacol. Ther"},{"key":"2020072821265814600_mvaa015-B30","first-page":"3786","article-title":"IL-1R1\/MyD88 signaling and the inflammasome are essential pulmonary inflammation and fibrosis in mice","volume":"117","author":"Gasse","year":"2007","journal-title":"J. Clin. Invest"},{"key":"2020072821265814600_mvaa015-B31","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2353\/ajpath.2008.070974","article-title":"Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling","volume":"173","author":"Bujak","year":"2008","journal-title":"Am. J. Pathol"},{"key":"2020072821265814600_mvaa015-B32","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00005-009-0024-y","article-title":"The role of IL-1 in the pathogenesis of heart disease","volume":"57","author":"Bujak","year":"2009","journal-title":"Arch. Immunol. Ther. Exp. (Warsz)"},{"key":"2020072821265814600_mvaa015-B33","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00281-016-0559-z","article-title":"The IL-1 cytokine family and its role in inflammation and fibrosis in the lung","volume":"38","author":"Borthwick","year":"2016","journal-title":"Semin. Immunopathol"},{"key":"2020072821265814600_mvaa015-B34","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1172\/JCI12568","article-title":"Transient expression of IL-1\u03b2 induces acute lung injury and chronic repair leading to pulmonary fibrosis","volume":"107","author":"Kolb","year":"2001","journal-title":"J. Clin. Invest"},{"key":"2020072821265814600_mvaa015-B35","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.imbio.2012.05.026","article-title":"IL-1\u03b2 and TGF\u03b22 synergistically induce endothelial to mesenchymal transition in an NF\u03baB-dependent manner","volume":"218","author":"Maleszewska","year":"2013","journal-title":"Immunobiology"}],"container-title":["The Journal of Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jb\/advance-article-pdf\/doi\/10.1093\/jb\/mvaa015\/32324172\/mvaa015.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jb\/article-pdf\/168\/2\/113\/33540520\/mvaa015.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jb\/article-pdf\/168\/2\/113\/33540520\/mvaa015.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T01:27:23Z","timestamp":1595986043000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jb\/article\/168\/2\/113\/5722206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,4]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2,4]]},"published-print":{"date-parts":[[2020,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jb\/mvaa015","relation":{},"ISSN":["0021-924X","1756-2651"],"issn-type":[{"value":"0021-924X","type":"print"},{"value":"1756-2651","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,8]]},"published":{"date-parts":[[2020,2,4]]}}}