{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:46:35Z","timestamp":1792165595600,"version":"4.4.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2019,5,24]],"date-time":"2019-05-24T00:00:00Z","timestamp":1558656000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,5,24]],"date-time":"2019-05-24T00:00:00Z","timestamp":1558656000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:p>\n                    Wnt signaling is one of the key regulators of hepatocellular carcinoma (HCC) tumor progression. In addition to the classical receptor frizzled (FZD), various coreceptors including heparan sulfate proteoglycans (HSPGs) are involved in Wnt activation. Glypican\u20103 (GPC3) is an HSPG that is overexpressed in HCC and functions as a Wnt coreceptor that modulates HCC cell proliferation. These features make GPC3 an attractive target for liver cancer therapy. However, the precise interaction of GPC3 and Wnt and how GPC3, Wnt, and FZD cooperate with each other are poorly understood. In this study, we established a structural model of GPC3 containing a putative FZD\u2010like cysteine\u2010rich domain at its N\u2010terminal lobe. We found that F41 and its surrounding residues in GPC3 formed a Wnt\u2010binding groove that interacted with the middle region located between the lipid thumb domain and the index finger domain of Wnt3a. Mutating residues in this groove significantly inhibited Wnt3a binding, \u03b2\u2010catenin activation, and the transcriptional activation of Wnt\u2010dependent genes. In contrast with the heparan sulfate chains, the Wnt\u2010binding groove that we identified in the protein core of GPC3 seemed to promote Wnt signaling in conditions when FZD was not abundant. Specifically, blocking this domain using an antibody inhibited Wnt activation. In HCC cells, mutating residue F41 on GPC3 inhibited activation of \u03b2\u2010catenin\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    and reduced xenograft tumor growth in nude mice compared with cells expressing wild\u2010type GPC3.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : Our investigation demonstrates a detailed interaction of GPC3 and Wnt3a, reveals the precise mechanism of GPC3 acting as a Wnt coreceptor, and provides a potential target site on GPC3 for Wnt blocking and HCC therapy.\n                  <\/jats:p>","DOI":"10.1002\/hep.30646","type":"journal-article","created":{"date-parts":[[2019,4,9]],"date-time":"2019-04-09T03:35:16Z","timestamp":1554780916000},"page":"1231-1245","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":113,"title":["A Frizzled\u2010Like Cysteine\u2010Rich Domain in Glypican\u20103 Mediates Wnt Binding and Regulates Hepatocellular Carcinoma Tumor Growth in Mice"],"prefix":"10.1097","volume":"70","author":[{"given":"Na","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Human Functional Genomics of Jiangsu Province, National Health Commission Key Laboratory of Antibody Techniques, School of Basic Medical Sciences,Nanjing Medical University,Nanjing,Jiangsu,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwen","family":"Wei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Human Functional Genomics of Jiangsu Province, National Health Commission Key Laboratory of Antibody Techniques, School of Basic Medical Sciences,Nanjing Medical University,Nanjing,Jiangsu,China"},{"name":"Bio\u2010medical Center, College of Life Science and Technology,Huazhong Agricultural University,Wuhan,Hubei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Human Functional Genomics of Jiangsu Province, National Health Commission Key Laboratory of Antibody Techniques, School of Basic Medical Sciences,Nanjing Medical University,Nanjing,Jiangsu,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjun","family":"Bai","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Ye","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda,MD"},{"name":"School of Life Sciences,East China Normal University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Baxa","sequence":"additional","affiliation":[{"name":"Electron Microscopy Laboratory,Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research,Frederick,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Sciences,East China Normal University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Lv","sequence":"additional","affiliation":[{"name":"Liver Transplantation Center of the First Affiliated Hospital,Nanjing Medical University,Nanjing,Jiangsu Province,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences,Nanjing Medical University,Nanjing,Jiangsu,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingqian","family":"Feng","sequence":"additional","affiliation":[{"name":"Bio\u2010medical Center, College of Life Science and Technology,Huazhong Agricultural University,Wuhan,Hubei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byungkook","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Human Functional Genomics of Jiangsu Province, National Health Commission Key Laboratory of Antibody Techniques, School of Basic Medical Sciences,Nanjing Medical University,Nanjing,Jiangsu,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9152-5405","authenticated-orcid":false,"given":"Mitchell","family":"Ho","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Center for Cancer Research,National Cancer Institute, National Institutes of 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