Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling
Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecula...
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| Veröffentlicht in: | Oncogene 2014-07, Vol.33 (30), p.3970-3979 |
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| creator | Kumar, S Pan, C C Bloodworth, J C Nixon, A B Theuer, C Hoyt, D G Lee, N Y |
| description | Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell–cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis. |
| doi_str_mv | 10.1038/onc.2013.386 |
| format | Article |
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A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell–cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2013.386</identifier><identifier>PMID: 24077288</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/45/127/1219 ; 631/80/86 ; 692/699/67/2328 ; Angiogenesis Inhibitors - pharmacology ; Animals ; Antibodies ; Antibodies, Monoclonal - pharmacology ; Antigens, CD - metabolism ; Apoptosis ; Cell Biology ; Cell Membrane - metabolism ; Cell Movement - drug effects ; Cellular signal transduction ; Cercopithecus aethiops ; COS Cells ; Drug Screening Assays, Antitumor ; Endoglin ; Human Genetics ; Human Umbilical Vein Endothelial Cells - drug effects ; Human Umbilical Vein Endothelial Cells - physiology ; Humans ; Internal Medicine ; Matrix Metalloproteinase 14 - metabolism ; Medicine ; Medicine & Public Health ; Neovascularization ; Neovascularization, Pathologic - prevention & control ; Oncology ; Original ; original-article ; Physiological aspects ; Protein Transport ; Proteolysis ; Receptors, Cell Surface - metabolism ; Signal Transduction ; Smad Proteins - metabolism ; Transforming Growth Factor beta - metabolism ; Transforming growth factors ; Viral antibodies</subject><ispartof>Oncogene, 2014-07, Vol.33 (30), p.3970-3979</ispartof><rights>The Author(s) 2014</rights><rights>COPYRIGHT 2014 Nature Publishing Group</rights><rights>Copyright © 2014 Macmillan Publishers Limited 2014 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-95789da2715bf84b3cdf0655f14879d20468f0a314bcd2450efb5d2c4cfd39b73</citedby><cites>FETCH-LOGICAL-c592t-95789da2715bf84b3cdf0655f14879d20468f0a314bcd2450efb5d2c4cfd39b73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27928,27929</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24077288$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kumar, S</creatorcontrib><creatorcontrib>Pan, C C</creatorcontrib><creatorcontrib>Bloodworth, J C</creatorcontrib><creatorcontrib>Nixon, A B</creatorcontrib><creatorcontrib>Theuer, C</creatorcontrib><creatorcontrib>Hoyt, D G</creatorcontrib><creatorcontrib>Lee, N Y</creatorcontrib><title>Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. 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Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell–cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis.</description><subject>631/45/127/1219</subject><subject>631/80/86</subject><subject>692/699/67/2328</subject><subject>Angiogenesis Inhibitors - pharmacology</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antigens, CD - metabolism</subject><subject>Apoptosis</subject><subject>Cell Biology</subject><subject>Cell Membrane - metabolism</subject><subject>Cell Movement - drug effects</subject><subject>Cellular signal transduction</subject><subject>Cercopithecus aethiops</subject><subject>COS Cells</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Endoglin</subject><subject>Human Genetics</subject><subject>Human Umbilical Vein Endothelial Cells - drug effects</subject><subject>Human Umbilical Vein Endothelial Cells - physiology</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Matrix Metalloproteinase 14 - metabolism</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Neovascularization</subject><subject>Neovascularization, Pathologic - prevention & control</subject><subject>Oncology</subject><subject>Original</subject><subject>original-article</subject><subject>Physiological aspects</subject><subject>Protein Transport</subject><subject>Proteolysis</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>Signal Transduction</subject><subject>Smad Proteins - metabolism</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Transforming growth factors</subject><subject>Viral antibodies</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNqNks1u1DAUhSMEokNhxxpZYsOiGfyb2BukUUULUitYlLXl-CfjktiDnVSaFe_Eg_SZcDSlUKkL5IVl3--cK1-fqnqN4BpBwt_HoNcYIrImvHlSrRBtm5oxQZ9WKygYrAUm-Kh6kfM1hLAVED-vjjCFbYs5X1U_N2HyXTT72vhk9WQN0HHeDT70IDpgg4l9OQAVDLi8_FojCnwGCny3ezBavVXB5xG4mP6ieWuNWfSLxthk-3lQk49hMbw6P6tvf4Hs-6CWJi-rZ04N2b6624-rb2cfr04_1Rdfzj-fbi5qzQSeasFaLozCLWKd47Qj2jjYMOYQ5a0wGNKGO6gIop02mDJoXccM1lQ7Q0TXkuPqw8F3N3ejNdqGKalB7pIfVdrLqLx8WAl-K_t4I4loBBeLwbs7gxR_zDZPcvRZ22FQwcY5S8QYLeNuIP4PlPKGMEFIQd8e0F4NVvrgYmmuF1xuCIcMNxjCQq0focoydvQ6But8uX8gODkIdIo5J-vuH4qgXFIjS2rkkhpZUlPwN_8O5x7-E5MC1Acgl1LobZLXcU7lB_Pjhr8BYHvMvQ</recordid><startdate>20140724</startdate><enddate>20140724</enddate><creator>Kumar, S</creator><creator>Pan, C C</creator><creator>Bloodworth, J C</creator><creator>Nixon, A B</creator><creator>Theuer, C</creator><creator>Hoyt, D G</creator><creator>Lee, N Y</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20140724</creationdate><title>Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling</title><author>Kumar, S ; Pan, C C ; Bloodworth, J C ; Nixon, A B ; Theuer, C ; Hoyt, D G ; Lee, N Y</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-95789da2715bf84b3cdf0655f14879d20468f0a314bcd2450efb5d2c4cfd39b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>631/45/127/1219</topic><topic>631/80/86</topic><topic>692/699/67/2328</topic><topic>Angiogenesis Inhibitors - pharmacology</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antigens, CD - metabolism</topic><topic>Apoptosis</topic><topic>Cell Biology</topic><topic>Cell Membrane - metabolism</topic><topic>Cell Movement - drug effects</topic><topic>Cellular signal transduction</topic><topic>Cercopithecus aethiops</topic><topic>COS Cells</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Endoglin</topic><topic>Human Genetics</topic><topic>Human Umbilical Vein Endothelial Cells - drug effects</topic><topic>Human Umbilical Vein Endothelial Cells - physiology</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Matrix Metalloproteinase 14 - metabolism</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Neovascularization</topic><topic>Neovascularization, Pathologic - prevention & control</topic><topic>Oncology</topic><topic>Original</topic><topic>original-article</topic><topic>Physiological aspects</topic><topic>Protein Transport</topic><topic>Proteolysis</topic><topic>Receptors, Cell Surface - metabolism</topic><topic>Signal Transduction</topic><topic>Smad Proteins - metabolism</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Transforming growth factors</topic><topic>Viral antibodies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kumar, S</creatorcontrib><creatorcontrib>Pan, C C</creatorcontrib><creatorcontrib>Bloodworth, J C</creatorcontrib><creatorcontrib>Nixon, A B</creatorcontrib><creatorcontrib>Theuer, C</creatorcontrib><creatorcontrib>Hoyt, D G</creatorcontrib><creatorcontrib>Lee, N Y</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumar, S</au><au>Pan, C C</au><au>Bloodworth, J C</au><au>Nixon, A B</au><au>Theuer, C</au><au>Hoyt, D G</au><au>Lee, N Y</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2014-07-24</date><risdate>2014</risdate><volume>33</volume><issue>30</issue><spage>3970</spage><epage>3979</epage><pages>3970-3979</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell–cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24077288</pmid><doi>10.1038/onc.2013.386</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/45/127/1219 631/80/86 692/699/67/2328 Angiogenesis Inhibitors - pharmacology Animals Antibodies Antibodies, Monoclonal - pharmacology Antigens, CD - metabolism Apoptosis Cell Biology Cell Membrane - metabolism Cell Movement - drug effects Cellular signal transduction Cercopithecus aethiops COS Cells Drug Screening Assays, Antitumor Endoglin Human Genetics Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - physiology Humans Internal Medicine Matrix Metalloproteinase 14 - metabolism Medicine Medicine & Public Health Neovascularization Neovascularization, Pathologic - prevention & control Oncology Original original-article Physiological aspects Protein Transport Proteolysis Receptors, Cell Surface - metabolism Signal Transduction Smad Proteins - metabolism Transforming Growth Factor beta - metabolism Transforming growth factors Viral antibodies |
| title | Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling |
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