{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T06:12:08Z","timestamp":1774505528822,"version":"3.50.1"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T00:00:00Z","timestamp":1635465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"the National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2011-0009719"],"award-info":[{"award-number":["2011-0009719"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"the National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2012M3A9C5048707"],"award-info":[{"award-number":["2012M3A9C5048707"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"the National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2020M3A9D5A01082439"],"award-info":[{"award-number":["2020M3A9D5A01082439"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"the National Research Foundation of Korea","doi-asserted-by":"crossref","award":["2019R1A2C2087198"],"award-info":[{"award-number":["2019R1A2C2087198"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>ERBB family members and their ligands play an essential role in embryonic heart development and adult heart physiology. Among them, ERBB3 is a binding partner of ERBB2; the ERBB2\/3 complex mediates downstream signaling for cell proliferation. ERBB3 has seven consensus binding sites to the p85 regulatory subunit of PI3K, which activates the downstream AKT pathway, leading to the proliferation of various cells. This study generated a human <jats:italic>ERBB3<\/jats:italic> knock-in mouse expressing a mutant ERBB3 whose seven YXXM p85 binding sites were replaced with YXXA. <jats:italic>Erbb3<\/jats:italic> knock-in embryos exhibited lethality between E12.5 to E13.5, and showed a decrease in mesenchymal cell numbers and density in AV cushions. We determined that the proliferation of mesenchymal cells in the atrioventricular (AV) cushion in <jats:italic>Erbb3<\/jats:italic> knock-in mutant embryos was temporarily reduced due to the decrease of AKT and ERK1\/2 phosphorylation. Overall, our results suggest that AKT\/ERK activation by the ERBB3-dependent PI3K signaling is crucial for AV cushion morphogenesis during embryonic heart development.<\/jats:p>","DOI":"10.1371\/journal.pone.0259426","type":"journal-article","created":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T17:27:53Z","timestamp":1635528473000},"page":"e0259426","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["ERBB3-dependent AKT and ERK pathways are essential for atrioventricular cushion development in mouse embryos"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0941-806X","authenticated-orcid":true,"given":"Kyoungmi","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daekee","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,10,29]]},"reference":[{"issue":"5","key":"pone.0259426.ref001","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nm0502-459","article-title":"ErbB2 is essential in the prevention of dilated cardiomyopathy","volume":"8","author":"SA Crone","year":"2002","journal-title":"Nat Med"},{"issue":"13","key":"pone.0259426.ref002","doi-asserted-by":"crossref","first-page":"8880","DOI":"10.1073\/pnas.122249299","article-title":"Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy.","volume":"99","author":"C Ozcelik","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"pone.0259426.ref003","doi-asserted-by":"crossref","first-page":"H1153","DOI":"10.1152\/ajpheart.00048.2005","article-title":"Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle","volume":"289","author":"H Garcia-Rivello","year":"2005","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"2","key":"pone.0259426.ref004","doi-asserted-by":"crossref","first-page":"H660","DOI":"10.1152\/ajpheart.00268.2005","article-title":"Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure","volume":"289","author":"FF Liu","year":"2005","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"pone.0259426.ref005","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1038\/msb4100012","article-title":"Phosphotyrosine interactome of the ErbB-receptor kinase family","volume":"1","author":"WX Schulze","year":"2005","journal-title":"Mol Syst Biol"},{"issue":"6","key":"pone.0259426.ref006","first-page":"3550","article-title":"3rd, Prigent SA, Gullick WG, Cantley LC. 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