{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360004236549525504.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1172/jci63836"}},{"identifier":{"@type":"URI","@value":"http://www.jci.org/articles/view/63836/files/pdf"}},{"identifier":{"@type":"PMID","@value":"23454766"}},{"identifier":{"@type":"HANDLE","@value":"10261/99338"}}],"resourceType":"学術雑誌論文(journal article)","dc:title":[{"@value":"IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver"}],"description":[{"notation":[{"@value":"In the tumor microenvironment, TGF-β induces transdifferentiation of quiescent pericytes and related stromal cells into myofibroblasts that promote tumor growth and metastasis. The mechanisms governing myofibroblastic activation remain poorly understood, and its role in the tumor microenvironment has not been explored. Here, we demonstrate that IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-β receptor II (TβRII) and suppresses TβRII-mediated signaling in pericytes to prevent myofibroblastic differentiation in the tumor microenvironment. We found that TGF-β1 recruited IQGAP1 to TβRII in hepatic stellate cells (HSCs), the resident liver pericytes. Iqgap1 knockdown inhibited the targeting of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor 1 (SMURF1) to the plasma membrane and TβRII ubiquitination and degradation. Thus, Iqgap1 knockdown stabilized TβRII and potentiated TGF-β1 transdifferentiation of pericytes into myofibroblasts in vitro. Iqgap1 deficiency in HSCs promoted myofibroblast activation, tumor implantation, and metastatic growth in mice via upregulation of paracrine signaling molecules. Additionally, we found that IQGAP1 expression was downregulated in myofibroblasts associated with human colorectal liver metastases. Taken together, our studies demonstrate that IQGAP1 in the tumor microenvironment suppresses TβRII and TGF-β dependent myofibroblastic differentiation to constrain tumor growth."}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380004236549525508","@type":"Researcher","foaf:name":[{"@value":"Chunsheng Liu"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236549525506","@type":"Researcher","foaf:name":[{"@value":"Daniel D. Billadeau"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236549525248","@type":"Researcher","foaf:name":[{"@value":"Haitham Abdelhakim"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236549525381","@type":"Researcher","foaf:name":[{"@value":"Edward Leof"}]},{"@id":"https://cir.nii.ac.jp/crid/1420001326226844160","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"00169377"},{"@type":"NRID","@value":"1000000169377"},{"@type":"NRID","@value":"9000002736882"},{"@type":"NRID","@value":"9000011010842"},{"@type":"NRID","@value":"9000014514968"},{"@type":"NRID","@value":"9000310741689"},{"@type":"NRID","@value":"9000002239045"},{"@type":"NRID","@value":"9000238171380"},{"@type":"NRID","@value":"9000408484895"},{"@type":"NRID","@value":"9000255950739"},{"@type":"NRID","@value":"9000402802662"},{"@type":"NRID","@value":"9000404100881"},{"@type":"NRID","@value":"9000255959971"},{"@type":"NRID","@value":"9000002159065"},{"@type":"NRID","@value":"9000255959924"},{"@type":"NRID","@value":"9000011192261"},{"@type":"NRID","@value":"9000408632372"},{"@type":"NRID","@value":"9000356514032"},{"@type":"NRID","@value":"9000361321065"},{"@type":"NRID","@value":"9000391614517"},{"@type":"NRID","@value":"9000408485231"},{"@type":"NRID","@value":"9000403959943"},{"@type":"NRID","@value":"9000253202309"},{"@type":"NRID","@value":"9000408480414"},{"@type":"NRID","@value":"9000302390650"},{"@type":"NRID","@value":"9000273020094"},{"@type":"NRID","@value":"9000253179117"},{"@type":"NRID","@value":"9000323829454"},{"@type":"NRID","@value":"9000298897758"},{"@type":"NRID","@value":"9000255959669"},{"@type":"NRID","@value":"9000410014880"},{"@type":"NRID","@value":"9000255679798"},{"@type":"NRID","@value":"9000262351841"},{"@type":"NRID","@value":"9000266427614"},{"@type":"NRID","@value":"9000011100621"},{"@type":"NRID","@value":"9000412058344"},{"@type":"NRID","@value":"9000018468716"},{"@type":"NRID","@value":"9000345338165"},{"@type":"NRID","@value":"9000399747880"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/kozokaibuchi"}],"foaf:name":[{"@value":"Kozo Kaibuchi"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236549525377","@type":"Researcher","foaf:name":[{"@value":"Carmelo Bernabeu"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236549525504","@type":"Researcher","foaf:name":[{"@value":"George S. Bloom"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236549525505","@type":"Researcher","foaf:name":[{"@value":"Liu Yang"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236549525379","@type":"Researcher","foaf:name":[{"@value":"Lisa Boardman"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236549525509","@type":"Researcher","foaf:name":[{"@value":"Vijay H. Shah"}]},{"@id":"https://cir.nii.ac.jp/crid/1380004236549525378","@type":"Researcher","foaf:name":[{"@value":"Ningling Kang"}]}],"contributor":[{"@id":"https://cir.nii.ac.jp/crid/1892555066089301888","@type":"Researcher","foaf:name":[{"@value":"Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"00219738"}],"prism:publicationName":[{"@value":"Journal of Clinical Investigation"}],"dc:publisher":[{"@value":"American Society for Clinical Investigation"}],"prism:publicationDate":"2013-02-01","prism:volume":"123","prism:number":"3","prism:startingPage":"1138","prism:endingPage":"1156"},"reviewed":"false","dcterms:accessRights":"http://purl.org/coar/access_right/c_abf2","url":[{"@id":"http://www.jci.org/articles/view/63836/files/pdf"}],"createdAt":"2013-03-02","modifiedAt":"2023-08-03","foaf:topic":[{"@id":"https://cir.nii.ac.jp/all?q=Adult","dc:title":"Adult"},{"@id":"https://cir.nii.ac.jp/all?q=Male","dc:title":"Male"},{"@id":"https://cir.nii.ac.jp/all?q=Cell%20Survival","dc:title":"Cell Survival"},{"@id":"https://cir.nii.ac.jp/all?q=Ubiquitin-Protein%20Ligases","dc:title":"Ubiquitin-Protein Ligases"},{"@id":"https://cir.nii.ac.jp/all?q=Mice,%20Nude","dc:title":"Mice, Nude"},{"@id":"https://cir.nii.ac.jp/all?q=Endosomes","dc:title":"Endosomes"},{"@id":"https://cir.nii.ac.jp/all?q=Protein%20Serine-Threonine%20Kinases","dc:title":"Protein Serine-Threonine Kinases"},{"@id":"https://cir.nii.ac.jp/all?q=Transforming%20Growth%20Factor%20beta1","dc:title":"Transforming Growth Factor beta1"},{"@id":"https://cir.nii.ac.jp/all?q=Mice","dc:title":"Mice"},{"@id":"https://cir.nii.ac.jp/all?q=Cell%20Movement","dc:title":"Cell Movement"},{"@id":"https://cir.nii.ac.jp/all?q=Hepatic%20Stellate%20Cells","dc:title":"Hepatic Stellate Cells"},{"@id":"https://cir.nii.ac.jp/all?q=Tumor%20Cells,%20Cultured","dc:title":"Tumor Cells, Cultured"},{"@id":"https://cir.nii.ac.jp/all?q=Animals","dc:title":"Animals"},{"@id":"https://cir.nii.ac.jp/all?q=Humans","dc:title":"Humans"},{"@id":"https://cir.nii.ac.jp/all?q=Protein%20Interaction%20Domains%20and%20Motifs","dc:title":"Protein Interaction Domains and Motifs"},{"@id":"https://cir.nii.ac.jp/all?q=Myofibroblasts","dc:title":"Myofibroblasts"},{"@id":"https://cir.nii.ac.jp/all?q=Aged","dc:title":"Aged"},{"@id":"https://cir.nii.ac.jp/all?q=Cell%20Proliferation","dc:title":"Cell Proliferation"},{"@id":"https://cir.nii.ac.jp/all?q=Aged,%2080%20and%20over","dc:title":"Aged, 80 and over"},{"@id":"https://cir.nii.ac.jp/all?q=Protein%20Stability","dc:title":"Protein Stability"},{"@id":"https://cir.nii.ac.jp/all?q=Liver%20Neoplasms","dc:title":"Liver Neoplasms"},{"@id":"https://cir.nii.ac.jp/all?q=Receptor,%20Transforming%20Growth%20Factor-beta%20Type%20II","dc:title":"Receptor, Transforming Growth Factor-beta Type II"},{"@id":"https://cir.nii.ac.jp/all?q=Ubiquitination","dc:title":"Ubiquitination"},{"@id":"https://cir.nii.ac.jp/all?q=Middle%20Aged","dc:title":"Middle Aged"},{"@id":"https://cir.nii.ac.jp/all?q=Tumor%20Burden","dc:title":"Tumor Burden"},{"@id":"https://cir.nii.ac.jp/all?q=Protein%20Transport","dc:title":"Protein Transport"},{"@id":"https://cir.nii.ac.jp/all?q=Liver","dc:title":"Liver"},{"@id":"https://cir.nii.ac.jp/all?q=ras%20GTPase-Activating%20Proteins","dc:title":"ras GTPase-Activating Proteins"},{"@id":"https://cir.nii.ac.jp/all?q=Cell%20Transdifferentiation","dc:title":"Cell Transdifferentiation"},{"@id":"https://cir.nii.ac.jp/all?q=Proteolysis","dc:title":"Proteolysis"},{"@id":"https://cir.nii.ac.jp/all?q=Female","dc:title":"Female"},{"@id":"https://cir.nii.ac.jp/all?q=Colorectal%20Neoplasms","dc:title":"Colorectal Neoplasms"},{"@id":"https://cir.nii.ac.jp/all?q=Lysosomes","dc:title":"Lysosomes"},{"@id":"https://cir.nii.ac.jp/all?q=Pericytes","dc:title":"Pericytes"},{"@id":"https://cir.nii.ac.jp/all?q=Receptors,%20Transforming%20Growth%20Factor%20beta","dc:title":"Receptors, Transforming Growth Factor beta"},{"@id":"https://cir.nii.ac.jp/all?q=Neoplasm%20Transplantation","dc:title":"Neoplasm Transplantation"},{"@id":"https://cir.nii.ac.jp/all?q=Protein%20Binding","dc:title":"Protein Binding"}],"project":[{"@id":"https://cir.nii.ac.jp/crid/1040282257005740160","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"20227006"},{"@type":"JGN","@value":"JP20227006"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20227006/"}],"notation":[{"@language":"ja","@value":"遊走細胞と神経細胞の極性形成を制御する分子ネットワーク"},{"@language":"en","@value":"MOLECULAR MECHANISMS UNDERLYING CELL POLARIZATION IN MIGRATING CELLS AND NEURONS"}]}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1050564285688017024","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@language":"en","@value":"Genetic and epigenetic signatures in human hepatocellular carcinoma: a systematic review."}]},{"@id":"https://cir.nii.ac.jp/crid/1360002214561710592","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Fatty liver creates a pro‐metastatic 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Function"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544418510139264","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Direct Interaction between Endothelial Nitric-oxide Synthase and Dynamin-2"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544418684277760","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The Prometastatic Microenvironment of the Liver"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544419420613632","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"IQGAP1 Stimulates Proliferation and Enhances Tumorigenesis of Human Breast Epithelial Cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544419604418816","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"TGFβ in Cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544420274551680","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Evolving challenges in hepatic 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