{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T16:50:11Z","timestamp":1793379011837,"version":"4.5.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000850","name":"National Heart and Lung Institute","doi-asserted-by":"publisher","award":["HL117247"],"award-info":[{"award-number":["HL117247"]}],"id":[{"id":"10.13039\/501100000850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000850","name":"National Heart and Lung Institute","doi-asserted-by":"publisher","award":["HL119053"],"award-info":[{"award-number":["HL119053"]}],"id":[{"id":"10.13039\/501100000850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000850","name":"National Heart and Lung Institute","doi-asserted-by":"publisher","award":["HL135854"],"award-info":[{"award-number":["HL135854"]}],"id":[{"id":"10.13039\/501100000850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000850","name":"National Heart and Lung Institute","doi-asserted-by":"publisher","award":["HL147313"],"award-info":[{"award-number":["HL147313"]}],"id":[{"id":"10.13039\/501100000850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000850","name":"National Heart and Lung Institute","doi-asserted-by":"publisher","award":["HL117247"],"award-info":[{"award-number":["HL117247"]}],"id":[{"id":"10.13039\/501100000850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000850","name":"National Heart and Lung Institute","doi-asserted-by":"publisher","award":["HL119053"],"award-info":[{"award-number":["HL119053"]}],"id":[{"id":"10.13039\/501100000850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000850","name":"National Heart and Lung Institute","doi-asserted-by":"publisher","award":["HL135854"],"award-info":[{"award-number":["HL135854"]}],"id":[{"id":"10.13039\/501100000850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000850","name":"National Heart and Lung Institute","doi-asserted-by":"publisher","award":["HL147313"],"award-info":[{"award-number":["HL147313"]}],"id":[{"id":"10.13039\/501100000850","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Epithelial\u2013mesenchymal transition (EMT) contributes to airway remodeling, a predominant feature of asthma. DOCK2 (dedicator of cytokinesis 2) is an innate immune signaling molecule involved in vascular remodeling. However, it is unknown if DOCK2 plays a role in airway remodeling during asthma development. In this study, we found that DOCK2 is highly induced in both normal human bronchial epithelial cells treated with house dust mite (HDM) extract and human asthmatic airway epithelium. DOCK2 is also upregulated by TGF-\u03b21 (transforming growth factor \u03b21) during EMT of human bronchial epithelial cells. Importantly, knockdown of DOCK2 inhibits, and overexpression of DOCK2 promotes, TGF-\u03b21\u2013induced EMT. Consistently, DOCK2 deficiency suppresses the EMT of airway epithelium, attenuates the subepithelial fibrosis, and improves pulmonary function in HDM-induced asthmatic lungs. These data suggest that DOCK2 plays an important role in EMT and asthma development. Mechanistically, DOCK2 interacts with transcription factor FoxM1 (forkhead box M1), which enhances FoxM1 binding to mesenchymal marker gene promoters and further promotes mesenchymal marker gene transcription and expression, leading to EMT. Taken together, our study identifies DOCK2 as a novel regulator for airway EMT in an HDM-induced asthma model, thus providing a potential therapeutic target for treatment of asthma.<\/jats:p>","DOI":"10.1165\/rcmb.2022-0273oc","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T10:06:47Z","timestamp":1678270007000},"page":"310-320","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":17,"title":["DOCK2 Promotes Asthma Development by Eliciting Airway Epithelial\u2013Mesenchymal Transition"],"prefix":"10.1093","volume":"69","author":[{"given":"Ning","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurological Intensive Care Unit, Taihe Hospital, Shiyan, China; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0297-8649","authenticated-orcid":false,"given":"Shi-You","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri"},{"name":"The Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,9,1]]},"reference":[{"key":"2026012204065635500_bib1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13223-018-0279-0","article-title":"Asthma","volume":"14","author":"Quirt","year":"2018","journal-title":"Allergy Asthma Clin Immunol"},{"key":"2026012204065635500_bib2","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fmed.2020.00191","article-title":"Airway remodeling in asthma","volume":"7","author":"Hough","year":"2020","journal-title":"Front Med (Lausanne)"},{"key":"2026012204065635500_bib3","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/MCP.0000000000000441","article-title":"Airway remodeling in asthma: update on mechanisms and therapeutic approaches","volume":"24","author":"Boulet","year":"2018","journal-title":"Curr Opin Pulm Med"},{"key":"2026012204065635500_bib4","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1165\/rcmb.2018-0169OC","article-title":"Autophagy activation in asthma airways remodeling","volume":"60","author":"McAlinden","year":"2019","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012204065635500_bib5","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1513\/pats.200907-067DP","article-title":"The role of the epithelium in airway remodeling in asthma","volume":"6","author":"Davies","year":"2009","journal-title":"Proc Am Thorac Soc"},{"key":"2026012204065635500_bib6","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1183\/09059180.00004413","article-title":"Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype","volume":"23","author":"Pain","year":"2014","journal-title":"Eur Respir Rev"},{"key":"2026012204065635500_bib7","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1136\/thoraxjnl-2013-204608","article-title":"Epithelial-mesenchymal transition in lung development and disease: does it exist and is it important?","volume":"69","author":"Bartis","year":"2014","journal-title":"Thorax"},{"key":"2026012204065635500_bib8","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/ACI.0b013e32834ec6eb","article-title":"Epithelial-mesenchymal transition in the pathophysiology of airway remodelling in asthma","volume":"12","author":"Hackett","year":"2012","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"2026012204065635500_bib9","doi-asserted-by":"crossref","first-page":"3305","DOI":"10.1073\/pnas.1113512109","article-title":"Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms","volume":"109","author":"Hanawa-Suetsugu","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026012204065635500_bib10","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/35090591","article-title":"Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration","volume":"412","author":"Fukui","year":"2001","journal-title":"Nature"},{"key":"2026012204065635500_bib11","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1093\/intimm\/dxz067","article-title":"DOCK family proteins: key players in immune surveillance mechanisms","volume":"32","author":"Kunimura","year":"2020","journal-title":"Int Immunol"},{"key":"2026012204065635500_bib12","doi-asserted-by":"crossref","first-page":"38","DOI":"10.15586\/aei.v50i3.543","article-title":"Dedicator of cytokinesis protein 2 knockdown ameliorates LPS-induced acute lung injury by modulating Rac1\/2 activity","volume":"50","author":"Zhou","year":"2022","journal-title":"Allergol Immunopathol (Madr)"},{"key":"2026012204065635500_bib13","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1161\/CIRCRESAHA.116.305863","article-title":"Dedicator of cytokinesis 2, a novel regulator for smooth muscle phenotypic modulation and vascular remodeling","volume":"116","author":"Guo","year":"2015","journal-title":"Circ Res"},{"key":"2026012204065635500_bib14","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1096\/fj.201600954r","article-title":"Runx2, a novel regulator for goblet cell differentiation and asthma development","volume":"31","author":"Shi","year":"2017","journal-title":"FASEB J"},{"key":"2026012204065635500_bib15","doi-asserted-by":"crossref","first-page":"4106","DOI":"10.1091\/mbc.e14-08-1255","article-title":"Olfactomedin 2, a novel regulator for transforming growth factor-\u03b2-induced smooth muscle differentiation of human embryonic stem cell-derived mesenchymal cells","volume":"25","author":"Shi","year":"2014","journal-title":"Mol Biol Cell"},{"key":"2026012204065635500_bib16","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1161\/ATVBAHA.116.308606","article-title":"Olfactomedin 2 regulates smooth muscle phenotypic modulation and vascular remodeling through mediating runt-related transcription factor 2 binding to serum response factor","volume":"37","author":"Shi","year":"2017","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026012204065635500_bib17","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2147\/JAA.S121092","article-title":"Animal models of asthma: utility and limitations","volume":"10","author":"Aun","year":"2017","journal-title":"J Asthma Allergy"},{"key":"2026012204065635500_bib18","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/978-1-4939-6786-5_10","article-title":"Murine models of allergic asthma","volume":"1559","author":"Haspeslagh","year":"2017","journal-title":"Methods Mol Biol"},{"key":"2026012204065635500_bib19","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1042\/CS20191309","article-title":"Bidirectional interaction of airway epithelial remodeling and inflammation in asthma","volume":"134","author":"Banno","year":"2020","journal-title":"Clin Sci (Lond)"},{"key":"2026012204065635500_bib20","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1165\/rcmb.2019-0395OC","article-title":"Impaired differentiation of chronic obstructive pulmonary disease bronchial epithelial cells grown on bronchial scaffolds","volume":"65","author":"Hedstr\u00f6m","year":"2021","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012204065635500_bib21","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/1465-9921-10-100","article-title":"TGF-beta1 induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells is enhanced by IL-1beta but not abrogated by corticosteroids","volume":"10","author":"Doerner","year":"2009","journal-title":"Respir Res"},{"key":"2026012204065635500_bib22","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1164\/rccm.200811-1730OC","article-title":"Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1","volume":"180","author":"Hackett","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026012204065635500_bib23","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12931-018-0834-8","article-title":"Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology","volume":"19","author":"Rout-Pitt","year":"2018","journal-title":"Respir Res"},{"key":"2026012204065635500_bib24","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.jaci.2005.07.011","article-title":"Airway remodeling contributes to the progressive loss of lung function in asthma: an overview","volume":"116","author":"Pascual","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"2026012204065635500_bib25","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1165\/rcmb.2021-0535OC","article-title":"Unique allergic asthma phenotypes in offspring of house dust mite-exposed mice","volume":"67","author":"Lebold","year":"2022","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012204065635500_bib26","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/emboj.2012.336","article-title":"Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition","volume":"32","author":"Balli","year":"2013","journal-title":"EMBO J"},{"key":"2026012204065635500_bib27","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s12964-019-0347-1","article-title":"The multifaceted roles of FOXM1 in pulmonary disease","volume":"17","author":"Li","year":"2019","journal-title":"Cell Commun Signal"},{"key":"2026012204065635500_bib28","doi-asserted-by":"crossref","first-page":"186","DOI":"10.7150\/ijbs.10634","article-title":"FOXM1 promotes lung adenocarcinoma invasion and metastasis by upregulating SNAIL","volume":"11","author":"Wei","year":"2015","journal-title":"Int J Biol Sci"},{"key":"2026012204065635500_bib29","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1172\/JCI87631","article-title":"FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis","volume":"128","author":"Penke","year":"2018","journal-title":"J Clin Invest"},{"key":"2026012204065635500_bib30","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.jphs.2020.05.007","article-title":"FoxM1 inhibition ameliorates renal interstitial fibrosis by decreasing extracellular matrix and epithelial-mesenchymal transition","volume":"143","author":"Wang","year":"2020","journal-title":"J Pharmacol Sci"},{"key":"2026012204065635500_bib31","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1128\/MCB.00881-12","article-title":"The forkhead transcription factor FOXM1 controls cell cycle-dependent gene expression through an atypical chromatin binding mechanism","volume":"33","author":"Chen","year":"2013","journal-title":"Mol Cell Biol"},{"key":"2026012204065635500_bib32","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1093\/nar\/gkab086","article-title":"Mechanism of forkhead transcription factors binding to a novel palindromic DNA site","volume":"49","author":"Li","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"2026012204065635500_bib33","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1165\/rcmb.2021-0175OC","article-title":"DOCK2 promotes pleural fibrosis by modulating mesothelial to mesenchymal transition","volume":"66","author":"Qian","year":"2022","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012204065635500_bib34","doi-asserted-by":"crossref","first-page":"9052","DOI":"10.1002\/jcp.27583","article-title":"Foxm1 is a critical driver of TGF-\u03b2-induced EndMT in endothelial cells through Smad2\/3 and binds to the Snail promoter","volume":"234","author":"Song","year":"2019","journal-title":"J Cell Physiol"},{"key":"2026012204065635500_bib35","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00441-016-2566-8","article-title":"Airway remodeling in asthma: what really matters","volume":"367","author":"Fehrenbach","year":"2017","journal-title":"Cell Tissue Res"},{"key":"2026012204065635500_bib36","doi-asserted-by":"crossref","first-page":"S143","DOI":"10.1513\/AnnalsATS.201802-128AW","article-title":"Airway epithelial differentiation and mucociliary clearance","volume":"15","author":"Whitsett","year":"2018","journal-title":"Ann Am Thorac Soc"},{"key":"2026012204065635500_bib37","doi-asserted-by":"crossref","first-page":"eaai8583","DOI":"10.1126\/scisignal.aai8583","article-title":"The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice","volume":"10","author":"Sun","year":"2017","journal-title":"Sci Signal"},{"key":"2026012204065635500_bib38","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1128\/MCB.00934-12","article-title":"FOXM1 promotes allergen-induced goblet cell metaplasia and pulmonary inflammation","volume":"33","author":"Ren","year":"2013","journal-title":"Mol Cell Biol"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/69\/3\/310\/66299701\/ajrcmb_69_3_310.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/69\/3\/310\/66299701\/ajrcmb_69_3_310.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T09:12:55Z","timestamp":1769073175000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/69\/3\/310\/8416777"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,1]]},"references-count":38,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,9,1]]},"published-print":{"date-parts":[[2023,9,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2022-0273oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,9]]},"published":{"date-parts":[[2023,9,1]]},"assertion":[{"value":"2022-07-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}