{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T13:36:10Z","timestamp":1770039370029,"version":"3.49.0"},"reference-count":29,"publisher":"The Company of Biologists","issue":"17","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["Z01DE0699"],"award-info":[{"award-number":["Z01DE0699"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["16H05175"],"award-info":[{"award-number":["16H05175"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["22K07154"],"award-info":[{"award-number":["22K07154"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Congenital tufting enteropathy (CTE) is a life-threatening intestinal disorder resulting from loss-of-function mutations in EPCAM and SPINT2. Mice deficient in Spint2, encoding the protease inhibitor HAI-2, develop CTE-like intestinal failure associated with a progressive loss of the EpCAM protein, which is caused by unchecked activity of the serine protease matriptase (ST14). Here, we show that loss of HAI-2 leads to increased proteolytic processing of EpCAM. Elimination of the reported matriptase cleavage site strongly suppressed proteolytic processing of EpCAM in vitro and in vivo. Unexpectedly, expression of cleavage-resistant EpCAM failed to prevent intestinal failure and postnatal lethality in Spint2-deficient mice. In addition, genetic inactivation of intestinal matriptase (St14) counteracted the effect of Spint2 deficiency in mice expressing cleavage-resistant EpCAM, indicating that matriptase does not drive intestinal dysfunction by excessive proteolysis of EpCAM. Interestingly, mice expressing cleavage-resistant EpCAM developed late-onset intestinal defects and exhibited a shortened lifespan even in the presence of HAI-2, suggesting that EpCAM cleavage is indispensable for EpCAM function. Our findings provide new insights into the role of EpCAM and the etiology of the enteropathies driven by Spint2 deficiency.<\/jats:p>","DOI":"10.1242\/dev.201801","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T09:44:09Z","timestamp":1691142249000},"source":"Crossref","is-referenced-by-count":1,"title":["Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM"],"prefix":"10.1242","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7661-8718","authenticated-orcid":false,"given":"Roman","family":"Szabo","sequence":"first","affiliation":[{"name":"National Institute of Dental and Craniofacial Research, National Institutes of Health 1 Proteases and Tissue Remodeling Section , , Bethesda, MD 20892 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8210-5460","authenticated-orcid":false,"given":"Makiko","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"University of Miyazaki 2 Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine , , Miyazaki 8891692 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9948-0451","authenticated-orcid":false,"given":"Hiroaki","family":"Kataoka","sequence":"additional","affiliation":[{"name":"University of Miyazaki 2 Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine , , Miyazaki 8891692 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7046-4060","authenticated-orcid":false,"given":"Thomas H.","family":"Bugge","sequence":"additional","affiliation":[{"name":"National Institute of Dental and Craniofacial Research, National Institutes of Health 1 Proteases and Tissue Remodeling Section , , Bethesda, MD 20892 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"key":"2023083111143760300_DEV201801C1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.4103\/1319-3767.203359","article-title":"New mutations of EpCAM gene for tufting enteropathy in Saudi Arabia","volume":"23","author":"Almahamed","year":"2017","journal-title":"Saudi J. 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