{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T03:45:44Z","timestamp":1792899944235,"version":"4.5.0"},"reference-count":71,"publisher":"American Society for Clinical Investigation","issue":"21","license":[{"start":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T00:00:00Z","timestamp":1731024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["NIH P30-AR069589"],"award-info":[{"award-number":["NIH P30-AR069589"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["NIH P30-AR075043"],"award-info":[{"award-number":["NIH P30-AR075043"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["NIH K08-AR075846"],"award-info":[{"award-number":["NIH K08-AR075846"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["NIH R03-AR082896"],"award-info":[{"award-number":["NIH R03-AR082896"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]},{"name":"University of Washington Institute for Stem Cell and Regenerative Medicine","award":["Innovation Pilot Award"],"award-info":[{"award-number":["Innovation Pilot Award"]}]},{"DOI":"10.13039\/100002886","name":"Foundation for Ichthyosis and Related Skin Types","doi-asserted-by":"crossref","award":["Research Grant"],"award-info":[{"award-number":["Research Grant"]}],"id":[{"id":"10.13039\/100002886","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Physician-Scientist Support Fund","award":["Medical Scholars Research Fellowship"],"award-info":[{"award-number":["Medical Scholars Research Fellowship"]}]},{"DOI":"10.13039\/100008456","name":"Taubman Medical Research Institute","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100008456","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,8]]},"abstract":"<jats:p>Grover disease is an acquired epidermal blistering disorder in which keratinocytes lose intercellular connections. While its pathologic features are well defined, its etiology remains unclear, and there is no FDA-approved therapy. Interestingly, Grover disease was a common adverse event in clinical trials for cancer using B-RAF inhibitors, but it remained unknown how B-RAF blockade compromised skin integrity. Here, we identified ERK hyperactivation as a key driver of Grover disease pathology. We leveraged a fluorescent biosensor to confirm that the B-RAF inhibitors dabrafenib and vemurafenib paradoxically activated ERK in human keratinocytes and organotypic epidermis, disrupting cell-cell junctions and weakening epithelial integrity. Consistent with clinical data showing that concomitant MEK blockade prevents Grover disease in patients receiving B-RAF inhibitors, we found that MEK inhibition suppressed ERK and rescued cohesion of B-RAF\u2013inhibited keratinocytes. Validating these results, we demonstrated ERK hyperactivation in patient biopsies from vemurafenib-induced Grover disease and from spontaneous Grover disease, revealing a common etiology for both. Finally, in line with our recent identification of ERK hyperactivation in Darier disease, a genetic disorder with identical pathology to Grover disease, our studies uncovered that the pathogenic mechanisms of these diseases converge on ERK signaling and support MEK inhibition as a therapeutic strategy.<\/jats:p>","DOI":"10.1172\/jci.insight.182983","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T12:00:53Z","timestamp":1727352053000},"source":"Crossref","is-referenced-by-count":12,"title":["ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3933-6404","authenticated-orcid":true,"given":"Cory L.","family":"Simpson","sequence":"first","affiliation":[{"name":"Department of Dermatology, and"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afua","family":"Tiwaa","sequence":"additional","affiliation":[{"name":"Department of Dermatology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivam A.","family":"Zaver","sequence":"additional","affiliation":[{"name":"Virginia Mason Medical Center, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Dermatology, and"},{"name":"University of Washington School of Medicine, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily Y.","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0802-2883","authenticated-orcid":true,"given":"Paul W.","family":"Harms","sequence":"additional","affiliation":[{"name":"Department of Pathology and"},{"name":"Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0080-0812","authenticated-orcid":true,"given":"Johann E.","family":"Gudjonsson","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2147\/CCID.S373228"},{"key":"B2"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2017.06.041"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.1970.04000040048010"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.5858\/133.9.1490"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.1971.04000190028005"},{"key":"B7","article-title":"Pumping the breaks on acantholytic skin disorders: targeting calcium pumps, desmosomes, and downstream signaling in Darier, Hailey-Hailey, and Grover disease","author":"Harmon","journal-title":"J Invest Dermatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/ddg.14202"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/ijd.14700"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/cup.13356"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.1977.01640040039004"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2023.1139"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/6784"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.9.1631"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(12)70413-8"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2012.04.008"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01244"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1203421"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1210093"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(12)70269-3"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nature08902"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1847"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.170739"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2015.1745"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0560.1995.tb01145.x"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3175"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-18-0048"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201710161"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65220"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200809044"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02883"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/mc.22644"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8738"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2014.21"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-380-0_10"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.07.014"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2006965117"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4161\/cc.6.23.4998"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-679X(04)78026-7"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.01.039"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-012-9488-y"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-013-0308-6"},{"key":"B43","first-page":"PO.18.00088","article-title":"Balancing RAF, MEK, and EGFR inhibitor doses to achieve clinical responses and modulate toxicity in BRAF V600E colorectal cancer","volume":"2018","author":"Mondaca","year":"2018","journal-title":"JCO Precis Oncol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003716200"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.168955"},{"issue":"4","key":"B46","first-page":"226","article-title":"Early growth response 1--a transcription factor in the crossfire of signal transduction cascades","volume":"48","author":"Pagel","year":"2011","journal-title":"Indian J Biochem Biophys"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2008.05.002"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2007.04.012"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.clindermatol.2020.03.006"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.det.2018.11.004"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/cea.14263"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2022.102292"},{"issue":"4","key":"B53","article-title":"Management and treatment of Grover\u2019s disease: a case report and review of literature","volume":"14","author":"Sousou","year":"2022","journal-title":"Cureus"},{"issue":"3","key":"B54","doi-asserted-by":"crossref","DOI":"10.5070\/D3253043336","article-title":"Persistent generalized Grover disease: complete remission after treatment with oral acitretin","volume":"25","author":"Pasmatzi","year":"2019","journal-title":"Dermatol Online J"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1177\/12034754231211567"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/S0190-9622(85)70124-7"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1111\/pde.14408"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1111\/ced.15382"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdcr.2022.01.029"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/dth.15429"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2020.5097"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1039\/D3MD00145H"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2303815"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00578-7"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.73.6785"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30679-4"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdcr.2023.06.038"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.2217\/fon.15.265"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1111\/ajd.12124"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108689"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.100397"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/182983\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T20:37:55Z","timestamp":1779136675000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/182983"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,8]]},"references-count":71,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11,8]]},"published-print":{"date-parts":[[2024,11,8]]}},"alternative-id":["10.1172\/jci.insight.182983"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.182983","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.04.30.591953","asserted-by":"object"}]},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,8]]},"article-number":"e182983"}}