{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:21:16Z","timestamp":1791220876244,"version":"4.1.0"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"8","license":[{"start":{"date-parts":[[2009,8,24]],"date-time":"2009-08-24T00:00:00Z","timestamp":1251072000000},"content-version":"vor","delay-in-days":181,"URL":"http:\/\/www.pnas.org\/site\/misc\/userlicense.xhtml"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,2,24]]},"abstract":"<jats:p>\n                    The activation of endothelin-A receptor (ET\n                    <jats:sub>A<\/jats:sub>\n                    R) by endothelin-1 (ET-1) has a critical role in ovarian tumorigenesis and progression. To define the molecular mechanism in ET-1-induced tumor invasion and metastasis, we focused on \u03b2-arrestins as scaffold and signaling proteins of G protein-coupled receptors. Here, we demonstrate that, in ovarian cancer cells, \u03b2-arrestin is recruited to ET\n                    <jats:sub>A<\/jats:sub>\n                    R to form two trimeric complexes: one through the interaction with Src leading to epithelial growth factor receptor (EGFR) transactivation and \u03b2-catenin Tyr phosphorylation, and the second through the physical association with axin, contributing to release and inactivation of glycogen synthase kinase (GSK)-3\u03b2 and \u03b2-catenin stabilization. The engagement of \u03b2-arrestin in these two signaling complexes concurs to activate \u03b2-catenin signaling pathways. We then demonstrate that silencing of both \u03b2-arrestin-1 and \u03b2-arrestin-2 inhibits ET\n                    <jats:sub>A<\/jats:sub>\n                    R-driven signaling, causing suppression of Src, mitogen-activated protein kinase (MAPK), AKT activation, as well as EGFR transactivation and a complete inhibition of ET-1-induced \u03b2-catenin\/TCF transcriptional activity and cell invasion. ET\n                    <jats:sub>A<\/jats:sub>\n                    R blockade with the specific ET\n                    <jats:sub>A<\/jats:sub>\n                    R antagonist ZD4054 abrogates the engagement of \u03b2-arrestin in the interplay between ET\n                    <jats:sub>A<\/jats:sub>\n                    R and the \u03b2-catenin pathway in the invasive program. Finally, ET\n                    <jats:sub>A<\/jats:sub>\n                    R is expressed in 85% of human ovarian cancers and is preferentially co-expressed with \u03b2-arrestin-1 in the advanced tumors. In a xenograft model of ovarian metastasis, HEY cancer cells expressing \u03b2-arrestin-1 mutant metastasize at a reduced rate, highlighting the importance of this molecule in promoting metastases. ZD4054 treatment significantly inhibits metastases, suggesting that specific ET\n                    <jats:sub>A<\/jats:sub>\n                    R antagonists, by disabling multiple signaling activated by ET\n                    <jats:sub>A<\/jats:sub>\n                    R\/\u03b2-arrestin, may represent new therapeutic opportunities for ovarian cancer.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0807158106","type":"journal-article","created":{"date-parts":[[2009,2,7]],"date-time":"2009-02-07T04:03:42Z","timestamp":1233979422000},"page":"2806-2811","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":153,"title":["\u03b2-Arrestin links endothelin A receptor to \u03b2-catenin signaling to induce ovarian cancer cell invasion and metastasis"],"prefix":"10.1073","volume":"106","author":[{"given":"Laura","family":"Rosan\u00f2","sequence":"first","affiliation":[{"name":"Laboratories of aMolecular Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Cianfrocca","sequence":"additional","affiliation":[{"name":"Laboratories of aMolecular Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Masi","sequence":"additional","affiliation":[{"name":"Laboratories of aMolecular Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Spinella","sequence":"additional","affiliation":[{"name":"Laboratories of aMolecular Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeriana","family":"Di Castro","sequence":"additional","affiliation":[{"name":"Laboratories of aMolecular Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Biroccio","sequence":"additional","affiliation":[{"name":"Experimental Chemotherapy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Salvati","sequence":"additional","affiliation":[{"name":"Experimental Chemotherapy, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rita","family":"Nicotra","sequence":"additional","affiliation":[{"name":"Molecular Biology and Pathology Institute, National Research Council, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Giorgio","family":"Natali","sequence":"additional","affiliation":[{"name":"Laboratories of aMolecular Pathology,"},{"name":"Molecular Biology and Pathology Institute, National Research Council, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Bagnato","sequence":"additional","affiliation":[{"name":"Laboratories of aMolecular Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,2,24]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0031-6997(25)06809-7","article-title":"Endothelins: Molecular biology, biochemistry, pharmacology, physiology and pathophysiology","volume":"46","author":"Rubanyi GM","year":"1994","unstructured":"GM Rubanyi, MA Polokoff, Endothelins: Molecular biology, biochemistry, pharmacology, physiology and pathophysiology. Pharmacol Rev 46, 325\u2013415 (1994).","journal-title":"Pharmacol Rev"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc990"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1677\/erc.1.01077"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64791-8"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.61.3.524"},{"key":"e_1_3_3_6_2","first-page":"8340","article-title":"Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells","volume":"61","author":"Rosan\u00f2 L","year":"2001","unstructured":"L Rosan\u00f2, et al., Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. Cancer Res 61, 8340\u20138346 (2001).","journal-title":"Cancer Res"},{"key":"e_1_3_3_7_2","first-page":"5310","article-title":"Transactivation of epidermal growth factor receptor in endothelin-1-induced mitogenic signaling in human ovarian carcinoma cells","volume":"60","author":"Vacca F","year":"2000","unstructured":"F Vacca, A Bagnato, CK Catt, R Tecce, Transactivation of epidermal growth factor receptor in endothelin-1-induced mitogenic signaling in human ovarian carcinoma cells. Cancer Res 60, 5310\u20135317 (2000).","journal-title":"Cancer Res"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0315"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2123"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304785200"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-05-0523"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207959"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00042.2007"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5402.655"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1109237"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31901"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510562103"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.211572798"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611356104"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000142200"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M910348199"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105364200"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.15.11312"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-0883"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.51.36734"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-6052"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601485"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1611"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-9046com"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.09.011"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508001200"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.262789099"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0807158106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T08:13:29Z","timestamp":1738916009000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0807158106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,24]]},"references-count":32,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2009,2,24]]}},"alternative-id":["10.1073\/pnas.0807158106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0807158106","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,2,24]]},"assertion":[{"value":"2008-07-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-02-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}