{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T08:07:31Z","timestamp":1789805251325,"version":"4.0.1"},"reference-count":47,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,8,15]]},"abstract":"<jats:p>Cell adhesion and migration are tightly controlled by regulated changes in the actin cytoskeleton. Previously we reported that the TGF\u03b2 (transforming growth factor \u03b2) superfamily co-receptor, T\u03b2RIII (type III TGF\u03b2 receptor; also known as betaglycan), regulates cell adhesion, migration and invasion, and suppresses cancer progression, in part, through activation of the small GTPase Cdc42 (cell division cycle 42), and Cdc42-dependent alterations to the actin cytoskeleton. In the present study we demonstrate that T\u03b2RIII specifically promotes filopodial formation and extension in MCF10A and HMEC (human mammary epithelial cell) mammary epithelial cells. Mechanistically, cell-surface T\u03b2RIII and Cdc42 co-localize to filopodial structures and co-complex in a \u03b2-arrestin2-dependent, and a T\u03b2RI\/T\u03b2RII-independent manner. The \u03b2-arrestin2-mediated interaction between T\u03b2RIII and Cdc42 increases complex formation between the Cdc42 effectors IRSp53 with N-WASP (neuronal Wiskott\u2013Aldrich syndrome protein) to increase filopodial formation. We demonstrate a function link between filopodial structures and epithelial cell adhesion as regulated by the T\u03b2RIII\u2013Cdc42 interaction. The present studies identify T\u03b2RIII as a novel regulator of IRSp53\/N-WASP via Cdc42 to regulate filopodial formation and cell adhesion.<\/jats:p>","DOI":"10.1042\/bj20121701","type":"journal-article","created":{"date-parts":[[2013,6,11]],"date-time":"2013-06-11T08:28:32Z","timestamp":1370939312000},"page":"79-89","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The type\u00a0III TGF\u03b2 receptor regulates filopodia formation via a Cdc42-mediated IRSp53\u2013N-WASP interaction in epithelial cells"],"prefix":"10.1042","volume":"454","author":[{"given":"Sun\u00a0Young","family":"Oh","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27708, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik\u00a0H.","family":"Knelson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27708, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard\u00a0C.","family":"Blobe","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27708, U.S.A."},{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27708, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthikeyan","family":"Mythreye","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27708, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2013,7,26]]},"reference":[{"key":"2021112215431038800_B1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.canlet.2012.03.024","article-title":"Targeting a cornerstone of radiation resistance: cancer stem cell","volume":"322","author":"Moncharmont","year":"2012","journal-title":"Cancer Lett."},{"key":"2021112215431038800_B2","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/1471-2407-11-88","article-title":"Downregulation of TGF-\u03b2 receptor types\u00a0II and III in oral squamous cell carcinoma and oral carcinoma-associated fibroblasts","volume":"11","author":"Meng","year":"2011","journal-title":"BMC Cancer"},{"key":"2021112215431038800_B3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0092-8674(95)90370-4","article-title":"Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia","volume":"81","author":"Nobes","year":"1995","journal-title":"Cell"},{"key":"2021112215431038800_B4","doi-asserted-by":"crossref","first-page":"9621","DOI":"10.1158\/0008-5472.CAN-10-1722","article-title":"Cancer exosomes trigger fibroblast to myofibroblast differentiation","volume":"70","author":"Webber","year":"2010","journal-title":"Cancer Res."},{"key":"2021112215431038800_B5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jcp.1095","article-title":"Endoglin: an accessory component of the TGF-\u03b2-binding receptor-complex with diagnostic, prognostic, and bioimmunotherapeutic potential in human malignancies","volume":"188","author":"Fonsatti","year":"2001","journal-title":"J. Cell. Physiol."},{"key":"2021112215431038800_B6","first-page":"105","article-title":"Neuropilin-1 is involved in regulation of apoptosis and migration of human colon cancer","volume":"29","author":"Ochiumi","year":"2006","journal-title":"Int. J. Oncol."},{"key":"2021112215431038800_B7","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1016\/S0960-9822(01)00506-1","article-title":"Cdc42 induces filopodia by promoting the formation of an IRSp53:Mena complex","volume":"11","author":"Krugmann","year":"2001","journal-title":"Curr. Biol."},{"key":"2021112215431038800_B8","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1046\/j.1523-1747.2000.00199.x","article-title":"Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor","volume":"115","author":"Lacal","year":"2000","journal-title":"J. Invest. Dermatol."},{"key":"2021112215431038800_B9","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.cellsig.2010.01.016","article-title":"Roles for the type\u00a0III TGF-\u03b2 receptor in human cancer","volume":"22","author":"Gatza","year":"2010","journal-title":"Cell. Signalling"},{"key":"2021112215431038800_B10","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1016\/0092-8674(93)90368-Z","article-title":"Betaglycan presents ligand to the TGF\u03b2 signaling receptor","volume":"73","author":"Lopez-Casillas","year":"1993","journal-title":"Cell"},{"key":"2021112215431038800_B11","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1126\/science.283.5410.2080","article-title":"Requirement of type\u00a0III TGF-\u03b2 receptor for endocardial cell transformation in the heart","volume":"283","author":"Brown","year":"1999","journal-title":"Science"},{"key":"2021112215431038800_B12","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1128\/MCB.23.12.4371-4385.2003","article-title":"Heart and liver defects and reduced transforming growth factor \u03b22 sensitivity in transforming growth factor \u03b2 type\u00a0III receptor-deficient embryos","volume":"23","author":"Stenvers","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"2021112215431038800_B13","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1172\/JCI29293","article-title":"The type\u00a0III TGF-\u03b2 receptor suppresses breast cancer progression","volume":"117","author":"Dong","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2021112215431038800_B14","doi-asserted-by":"crossref","first-page":"5231","DOI":"10.1158\/0008-5472.CAN-07-0035","article-title":"Loss of betaglycan expression in ovarian cancer: role in motility and invasion","volume":"67","author":"Hempel","year":"2007","journal-title":"Cancer Res."},{"key":"2021112215431038800_B15","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1399-0004.2007.00734.x","article-title":"ENG mutations in MADH4\/BMPR1A mutation negative patients with juvenile polyposis","volume":"71","author":"Howe","year":"2007","journal-title":"Clin. Genet."},{"key":"2021112215431038800_B16","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/carcin\/bgm249","article-title":"Loss of type\u00a0III transforming growth factor \u03b2 receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression","volume":"29","author":"Gordon","year":"2008","journal-title":"Carcinogenesis"},{"key":"2021112215431038800_B17","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1093\/carcin\/bgp271","article-title":"The type\u00a0III TGF-\u03b2 receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-\u03b2 signaling","volume":"31","author":"Lee","year":"2010","journal-title":"Carcinogenesis"},{"key":"2021112215431038800_B18","doi-asserted-by":"crossref","first-page":"8221","DOI":"10.1073\/pnas.0812879106","article-title":"The type\u00a0III TGF-\u03b2 receptor regulates epithelial and cancer cell migration through \u03b2-arrestin2-mediated activation of Cdc42","volume":"106","author":"Mythreye","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215431038800_B19","doi-asserted-by":"crossref","first-page":"7304","DOI":"10.1158\/0008-5472.CAN-07-6777","article-title":"Knockdown of the transforming growth factor-\u03b2 type\u00a0III receptor impairs motility and invasion of metastatic cancer cells","volume":"68","author":"Criswell","year":"2008","journal-title":"Cancer Res."},{"key":"2021112215431038800_B20","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1038\/onc.2012.157","article-title":"T\u03b2RIII\/\u03b2-arrestin2 regulates integrin \u03b15\u03b21 trafficking, function, and localization in epithelial cells","volume":"32","author":"Mythreye","year":"2012","journal-title":"Oncogene"},{"key":"2021112215431038800_B21","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nrc727","article-title":"Role of integrins in cell invasion and migration","volume":"2","author":"Hood","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"2021112215431038800_B22","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1101\/gad.828901","article-title":"Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells","volume":"15","author":"Elenbaas","year":"2001","journal-title":"Genes Dev."},{"key":"2021112215431038800_B23","first-page":"346","article-title":"Identification of a global gene expression signature of B-chronic lymphocytic leukemia","volume":"1","author":"Jelinek","year":"2003","journal-title":"Mol. Cancer Res."},{"key":"2021112215431038800_B24","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1083\/jcb.103.2.333","article-title":"Perinuclear location and recycling of epidermal growth factor receptor kinase: immunofluorescent visualization using antibodies directed to kinase and extracellular domains","volume":"103","author":"Murthy","year":"1986","journal-title":"J. Cell Biol."},{"key":"2021112215431038800_B25","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0960-9822(02)00423-2","article-title":"Two GTPases, Cdc42 and Rac, bind directly to a protein implicated in the immunodeficiency disorder Wiskott\u2013Aldrich syndrome","volume":"6","author":"Aspenstrom","year":"1996","journal-title":"Curr. Biol."},{"key":"2021112215431038800_B26","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1128\/MCB.25.5.1680-1695.2005","article-title":"Spatially distinct binding of Cdc42 to PAK1 and N-WASP in breast carcinoma cells","volume":"25","author":"Parsons","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"2021112215431038800_B27","doi-asserted-by":"crossref","first-page":"4018","DOI":"10.1038\/sj.emboj.7600386","article-title":"Endoglin promotes endothelial cell proliferation and TGF-\u03b2\/ALK1 signal transduction","volume":"23","author":"Lebrin","year":"2004","journal-title":"EMBO J."},{"key":"2021112215431038800_B28","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/0092-8674(92)90395-S","article-title":"TGF \u03b2 signals through a heteromeric protein kinase receptor complex","volume":"71","author":"Wrana","year":"1992","journal-title":"Cell"},{"key":"2021112215431038800_B29","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1126\/science.1083195","article-title":"\u03b2-Arrestin 2 mediates endocytosis of type\u00a0III TGF-\u03b2 receptor and down-regulation of its signaling","volume":"301","author":"Chen","year":"2003","journal-title":"Science"},{"key":"2021112215431038800_B30","doi-asserted-by":"crossref","first-page":"7628","DOI":"10.1074\/jbc.M704883200","article-title":"Bone morphogenetic proteins signal through the transforming growth factor-\u03b2 type\u00a0III receptor","volume":"283","author":"Kirkbride","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021112215431038800_B31","doi-asserted-by":"crossref","first-page":"39608","DOI":"10.1074\/jbc.M106831200","article-title":"A novel mechanism for regulating transforming growth factor \u03b2 (TGF-\u03b2) signaling. Functional modulation of type\u00a0III TGF-\u03b2 receptor expression through interaction with the PDZ domain protein, GIPC","volume":"276","author":"Blobe","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021112215431038800_B32","first-page":"1601","article-title":"\u03b2-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking","volume":"98","author":"Kohout","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215431038800_B33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000097040","article-title":"Reduced tumor growth and angiogenesis in endoglin-haploinsufficient mice","volume":"28","author":"Duwel","year":"2007","journal-title":"Tumor Biol."},{"key":"2021112215431038800_B34","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1083\/jcb.201007002","article-title":"The serine\/threonine kinase Par1b regulates epithelial lumen polarity via IRSp53-mediated cell-ECM signaling","volume":"192","author":"Cohen","year":"2011","journal-title":"J. Cell Biol."},{"key":"2021112215431038800_B35","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1042\/bj3480241","article-title":"Rho GTPases and their effector proteins","volume":"348","author":"Bishop","year":"2000","journal-title":"Biochem. J."},{"key":"2021112215431038800_B36","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1002\/ijc.23314","article-title":"Anti-tumor activity of an anti-endoglin monoclonal antibody is enhanced in immunocompetent mice","volume":"122","author":"Tsujie","year":"2008","journal-title":"Int. J. Cancer"},{"key":"2021112215431038800_B37","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/ijc.10611","article-title":"Neuropilin-1 is differentially expressed in myoepithelial cells and vascular smooth muscle cells in preneoplastic and neoplastic human breast: a possible marker for the progression of breast cancer","volume":"101","author":"Stephenson","year":"2002","journal-title":"Int. J. Cancer"},{"key":"2021112215431038800_B38","doi-asserted-by":"crossref","first-page":"3892","DOI":"10.1182\/blood-2005-10-4113","article-title":"Ligand-induced internalization selects use of common receptor neuropilin-1 by VEGF165 and semaphorin3A","volume":"107","author":"Narazaki","year":"2006","journal-title":"Blood"},{"key":"2021112215431038800_B39","doi-asserted-by":"crossref","first-page":"56","DOI":"10.4161\/cam.1.2.4490","article-title":"Neuropilins: novel targets for anti-angiogenesis therapies","volume":"1","author":"Geretti","year":"2007","journal-title":"Cell Adhes. Migr."},{"key":"2021112215431038800_B40","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1096\/fj.05-5229fje","article-title":"Identification of CD109 as part of the TGF-\u03b2 receptor system in human keratinocytes","volume":"20","author":"Finnson","year":"2006","journal-title":"FASEB J."},{"key":"2021112215431038800_B41","doi-asserted-by":"crossref","first-page":"29820","DOI":"10.1074\/jbc.M503511200","article-title":"Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor","volume":"280","author":"Babitt","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021112215431038800_B42","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1146\/annurev.biochem.67.1.753","article-title":"TGF-\u03b2 signal transduction","volume":"67","author":"Massague","year":"1998","journal-title":"Annu. Rev. Biochem."},{"key":"2021112215431038800_B43","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1091\/mbc.01-08-0398","article-title":"Transforming growth factor-\u03b2-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA","volume":"13","author":"Edlund","year":"2002","journal-title":"Mol. Biol. Cell"},{"key":"2021112215431038800_B44","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1182\/blood-2010-08-302034","article-title":"Sezary syndrome cells overexpress syndecan-4 bearing distinct heparan sulfate moieties that suppress T-cell activation by binding DC-HIL and trapping TGF-\u03b2 on the cell surface","volume":"117","author":"Chung","year":"2011","journal-title":"Blood"},{"key":"2021112215431038800_B45","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1093\/carcin\/bgp071","article-title":"The type\u00a0III transforming growth factor-\u03b2 receptor negatively regulates nuclear factor \u03baB signaling through its interaction with beta-arrestin2","volume":"30","author":"You","year":"2009","journal-title":"Carcinogenesis"},{"key":"2021112215431038800_B46","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/path.1312","article-title":"Proteoglycans and WT1 as markers for distinguishing adenocarcinoma, epithelioid mesothelioma, and benign mesothelium","volume":"199","author":"Gulyas","year":"2003","journal-title":"J. Pathol."},{"key":"2021112215431038800_B47","first-page":"1123","article-title":"Prognostic significance of altered expression of SDC2 and CYR61\u00a0in esophageal squamous cell carcinoma","volume":"21","author":"Huang","year":"2009","journal-title":"Oncol. Rep."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/454\/1\/79\/675475\/bj4540079.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/454\/1\/79\/675475\/bj4540079.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T21:58:33Z","timestamp":1637618313000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/454\/1\/79\/46295\/The-type-III-TGF-receptor-regulates-filopodia"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,7,26]]},"references-count":47,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,8,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20121701","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,7,26]]}}}