{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T01:29:58Z","timestamp":1785461398028,"version":"3.56.0"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:00:00Z","timestamp":1692576000000},"content-version":"vor","delay-in-days":232,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Reprod Medicine &amp; Biology"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Extravillous trophoblasts (EVTs) invade the endometrium to establish a fetomaternal interaction during pregnancy. Epidermal growth factor (EGF) and heparin\u2010binding EGF\u2010like growth factor (HB\u2010EGF) stimulate EVT invasion by binding to the EGF receptor (EGFR). We examined the role of the small GTP\u2010binding protein Rap1 in EGF\u2010 and HB\u2010EGF\u2010stimulated EVT invasion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Expression of Rap1 in the first\u2010trimester placenta was examined by immunohistochemistry. Effect of EGF or HB\u2010EGF on Rap1 activation (GTP\u2010Rap1) and Rap1 knockdown on invasion was assessed in EVT cell line (HTR\u20108\/SVneo). In addition, effect of Rap1 knockdown and Rap1GAP (a Rap1 inactivator) overexpression on the activation of EGF signaling and EGFR expression were examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Rap1 was expressed by EVTs, villous cytotrophoblasts, and syncytiotrophoblasts in the placenta. EGF and HB\u2010EGF activated Rap1 and promoted invasion of HTR\u20108\/SVneo, and these effects were inhibited by Rap1 knockdown. The EGF\u2010 and HB\u2010EGF\u2010induced phosphorylation of AKT, ERK1\/2, p38MAPK, and Src was inhibited by Rap1 knockdown. Furthermore, the knockdown of Rap1 reduced the EGFR protein level. Overexpression of Rap1GAP repressed EGF\u2010 and HB\u2010EGF\u2010induced Rap1 activation and reduced EGFR expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Rap1 may function as a mediator of EGF and HB\u2010EGF signaling pathways and can modulate EGFR expression in EVTs during placental development.<\/jats:p><\/jats:sec>","DOI":"10.1002\/rmb2.12537","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T07:38:07Z","timestamp":1692689887000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Small GTP\u2010binding protein Rap1 mediates EGF and HB\u2010EGF signaling and modulates EGF receptor expression in HTR\u20108\/SVneo extravillous trophoblast 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