{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:59:08Z","timestamp":1787018348557,"version":"build-2736575974"},"reference-count":26,"publisher":"American Society for Clinical Investigation","issue":"5","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Science Foundation of China","doi-asserted-by":"crossref","award":["82170300"],"award-info":[{"award-number":["82170300"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Key Research and Development Program of China","award":["2019YFA0802003"],"award-info":[{"award-number":["2019YFA0802003"]}]},{"name":"Australian National Heart Foundation Future Leader Fellowship","award":["101856"],"award-info":[{"award-number":["101856"]}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"crossref","award":["1158997,1158998"],"award-info":[{"award-number":["1158997,1158998"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,8]]},"abstract":"<jats:p>\n                    Loss-of-function mutations in cerebral cavernous malformation (CCM) genes and gain-of-function mutation in the\n                    <jats:italic>MAP3K3<\/jats:italic>\n                    gene encoding MEKK3 cause CCM. Deficiency of CCM proteins leads to the activation of MEKK3-KLF2\/4 signaling, but it is not clear how this occurs. Here, we demonstrate that deletion of the CCM3 interacting kinases STK24\/25 in endothelial cells causes defects in vascular patterning during development as well as CCM lesion formation during postnatal life. While permanent deletion of STK24\/25 in endothelial cells caused developmental defects of the vascular system, inducible postnatal deletion of STK24\/25 impaired angiogenesis in the retina and brain. More importantly, deletion of STK24\/25 in neonatal mice led to the development of severe CCM lesions. At the molecular level, a hybrid protein consisting of the STK kinase domain and the MEKK3 interacting domain of CCM2 rescued the vascular phenotype caused by the loss of\n                    <jats:italic>ccm<\/jats:italic>\n                    gene function in zebrafish. Our study suggests that CCM2\/3 proteins act as adapters to allow recruitment of STK24\/25 to limit the constitutive MEKK3 activity, thus contributing to vessel stability. Loss of STK24\/25 causes MEKK3 activation, leading to CCM lesion formation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.160372","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T12:01:06Z","timestamp":1674561666000},"source":"Crossref","is-referenced-by-count":19,"title":["Release of STK24\/25 suppression on MEKK3 signaling in endothelial cells confers cerebral cavernous malformation"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2386-267X","authenticated-orcid":true,"given":"Xi","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Ting","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1966-0485","authenticated-orcid":true,"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenkun","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiao","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8628-243X","authenticated-orcid":true,"given":"Xiaohong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6984-7192","authenticated-orcid":true,"given":"M. Lienhard","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Justus Liebig University, Member of the German Center for Lung Research, Giessen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renjing","family":"Liu","sequence":"additional","affiliation":[{"name":"Vascular Epigenetics Laboratory, Victor Chang Cardiac Research Institute, and St. Vincent\u2019s Clinical School, University of New South Wales, Sydney, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, and"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6277-5168","authenticated-orcid":true,"given":"Xiangjian","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, and Center for Cardiovascular Diseases, Tianjin Medical University, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.200263"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318174"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi256"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39679"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-007-0098-9"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201407129"},{"key":"B7","doi-asserted-by":"crossref","DOI":"10.3389\/fsurg.2016.00060","article-title":"Cerebral cavernous malformations: review of the genetic and protein-protein interactions resulting in disease pathogenesis","volume":"3","author":"Baranoski","year":"2016","journal-title":"Front Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.616433"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1071"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nature17178"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2014.12.009"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200140"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau0731"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.04.005"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M800266-MCP200"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01036"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1911"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110571"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44393"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4169"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nature12207"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.121.036940"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nature09002"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801474200"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.142838"},{"key":"B26"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/160372\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T21:56:42Z","timestamp":1779141402000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/160372"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,8]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3,8]]},"published-print":{"date-parts":[[2023,3,8]]}},"alternative-id":["10.1172\/jci.insight.160372"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.160372","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,8]]},"article-number":"e160372"}}