TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling
Growing evidence suggests that overexpression of TrkC, a member of the Trk family of neurotrophin receptors, could drive tumorigenesis, invasion and metastatic capability in cancer cells. However, relatively little is known about the mechanism of TrkC-mediated oncogenesis. The TrkC gene is a partner...
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| Veröffentlicht in: | Oncogene 2007-12, Vol.26 (55), p.7684-7691 |
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| creator | Jin, W Yun, C Kwak, M-K Kim, T-A Kim, S-J |
| description | Growing evidence suggests that overexpression of TrkC, a member of the Trk family of neurotrophin receptors, could drive tumorigenesis, invasion and metastatic capability in cancer cells. However, relatively little is known about the mechanism of TrkC-mediated oncogenesis. The TrkC gene is a partner of the Tel-TrkC (ETV6-NTRK3) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages. Recently, we have shown that ETV6-NTRK3 suppresses transforming growth factor-
β
(TGF-
β
) signaling by directly binding to the type II TGF-
β
receptor (T
β
RII). Here, we report that expression of TrkC also suppresses TGF-
β
-induced Smad2/3 phosphorylation and transcriptional activation. Silencing TrkC expression by small interfering RNA in the highly metastatic 4T1 mammary tumor cell line expressing endogenous TrkC significantly enhanced TGF-
β
-induced Smad2/3 phosphorylation and restored TGF-
β
growth inhibitory activity. In contrast, expression of TrkC in 67NR cells, in which TrkC is not expressed, suppressed TGF-
β
transcriptional activation. Moreover, we show that TrkC directly binds to the T
β
RII, thereby preventing it from interacting with the type I TGF-
β
receptor (T
β
RI). These results indicate that TrkC is an inhibitor of TGF-
β
tumor suppressor activity. |
| doi_str_mv | 10.1038/sj.onc.1210571 |
| format | Article |
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β
(TGF-
β
) signaling by directly binding to the type II TGF-
β
receptor (T
β
RII). Here, we report that expression of TrkC also suppresses TGF-
β
-induced Smad2/3 phosphorylation and transcriptional activation. Silencing TrkC expression by small interfering RNA in the highly metastatic 4T1 mammary tumor cell line expressing endogenous TrkC significantly enhanced TGF-
β
-induced Smad2/3 phosphorylation and restored TGF-
β
growth inhibitory activity. In contrast, expression of TrkC in 67NR cells, in which TrkC is not expressed, suppressed TGF-
β
transcriptional activation. Moreover, we show that TrkC directly binds to the T
β
RII, thereby preventing it from interacting with the type I TGF-
β
receptor (T
β
RI). These results indicate that TrkC is an inhibitor of TGF-
β
tumor suppressor activity.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1210571</identifier><identifier>PMID: 17546043</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Apoptosis ; Biological and medical sciences ; Cancer ; Care and treatment ; Cell Biology ; Cell Line, Tumor ; Cell physiology ; Cell receptors ; Cell structures and functions ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cellular signal transduction ; Fundamental and applied biological sciences. Psychology ; Gene silencing ; Genetic aspects ; Growth factor receptors ; Health aspects ; Human Genetics ; Humans ; Internal Medicine ; Kinases ; Mammary gland ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Mice ; Miscellaneous ; Molecular and cellular biology ; Neurotrophin receptors ; NIH 3T3 Cells ; Oncology ; original-article ; Phosphorylation ; Protein-Serine-Threonine Kinases - metabolism ; Protein-tyrosine kinase ; Receptor, trkC - antagonists & inhibitors ; Receptor, trkC - genetics ; Receptor, trkC - metabolism ; Receptors, Transforming Growth Factor beta - metabolism ; RNA, Small Interfering - pharmacology ; Signal Transduction ; siRNA ; Smad2 protein ; Smad2 Protein - metabolism ; Smad3 Protein - metabolism ; Transcription activation ; Transcriptional Activation ; Transforming Growth Factor beta - antagonists & inhibitors ; Transforming Growth Factor beta - metabolism ; Transforming Growth Factor beta - pharmacology ; Transforming growth factor-b ; TrkC receptors ; Tumor suppressor genes ; Tumor Suppressor Proteins - antagonists & inhibitors ; Tumor Suppressor Proteins - metabolism ; Tumor Suppressor Proteins - pharmacology ; Tumorigenesis ; Tumors</subject><ispartof>Oncogene, 2007-12, Vol.26 (55), p.7684-7691</ispartof><rights>Springer Nature Limited 2007</rights><rights>2008 INIST-CNRS</rights><rights>COPYRIGHT 2007 Nature Publishing Group</rights><rights>Nature Publishing Group 2007.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-e0a86242fa5a7dc85493878d5d560a0b1af307bfe5965a3d3c599385f0b8d893</citedby><cites>FETCH-LOGICAL-c498t-e0a86242fa5a7dc85493878d5d560a0b1af307bfe5965a3d3c599385f0b8d893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.onc.1210571$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.onc.1210571$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,778,782,27911,27912,41475,42544,51306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19925643$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17546043$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jin, W</creatorcontrib><creatorcontrib>Yun, C</creatorcontrib><creatorcontrib>Kwak, M-K</creatorcontrib><creatorcontrib>Kim, T-A</creatorcontrib><creatorcontrib>Kim, S-J</creatorcontrib><title>TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Growing evidence suggests that overexpression of TrkC, a member of the Trk family of neurotrophin receptors, could drive tumorigenesis, invasion and metastatic capability in cancer cells. However, relatively little is known about the mechanism of TrkC-mediated oncogenesis. The TrkC gene is a partner of the Tel-TrkC (ETV6-NTRK3) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages. Recently, we have shown that ETV6-NTRK3 suppresses transforming growth factor-
β
(TGF-
β
) signaling by directly binding to the type II TGF-
β
receptor (T
β
RII). Here, we report that expression of TrkC also suppresses TGF-
β
-induced Smad2/3 phosphorylation and transcriptional activation. Silencing TrkC expression by small interfering RNA in the highly metastatic 4T1 mammary tumor cell line expressing endogenous TrkC significantly enhanced TGF-
β
-induced Smad2/3 phosphorylation and restored TGF-
β
growth inhibitory activity. In contrast, expression of TrkC in 67NR cells, in which TrkC is not expressed, suppressed TGF-
β
transcriptional activation. Moreover, we show that TrkC directly binds to the T
β
RII, thereby preventing it from interacting with the type I TGF-
β
receptor (T
β
RI). These results indicate that TrkC is an inhibitor of TGF-
β
tumor suppressor activity.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell physiology</subject><subject>Cell receptors</subject><subject>Cell structures and functions</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Cellular signal transduction</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene silencing</subject><subject>Genetic aspects</subject><subject>Growth factor receptors</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Mammary gland</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Miscellaneous</subject><subject>Molecular and cellular biology</subject><subject>Neurotrophin receptors</subject><subject>NIH 3T3 Cells</subject><subject>Oncology</subject><subject>original-article</subject><subject>Phosphorylation</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Protein-tyrosine kinase</subject><subject>Receptor, trkC - antagonists & inhibitors</subject><subject>Receptor, trkC - genetics</subject><subject>Receptor, trkC - metabolism</subject><subject>Receptors, Transforming Growth Factor beta - metabolism</subject><subject>RNA, Small Interfering - pharmacology</subject><subject>Signal Transduction</subject><subject>siRNA</subject><subject>Smad2 protein</subject><subject>Smad2 Protein - metabolism</subject><subject>Smad3 Protein - metabolism</subject><subject>Transcription activation</subject><subject>Transcriptional Activation</subject><subject>Transforming Growth Factor beta - antagonists & inhibitors</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Transforming Growth Factor beta - pharmacology</subject><subject>Transforming growth factor-b</subject><subject>TrkC receptors</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Proteins - antagonists & inhibitors</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Tumor Suppressor Proteins - pharmacology</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp10UGP1CAUB3BiNO64evVomhi9dfZRoMBxM3HWSTbxMndCKR0ZO6Xy2sN-LT-In0nGrRlj1nAg4f14PPIn5C2FNQWmbvC4joNb04qCkPQZWVEu61IIzZ-TFWgBpa5YdUVeIR4BQGqoXpIrKgWvgbMV2e7Tt03RhKHFYorF9NUX08Poi92u2N9ty58_iuSdH6eYzmWcxzF5xD81DIfB9mE4vCYvOtujf7Ps12S__bTffC7vv9ztNrf3peNaTaUHq-qKV50VVrZOCa6ZkqoVrajBQkNtx0A2nRe6Fpa1zAmdheigUa3S7Jp8fGw7pvh99jiZU0Dn-94OPs5oag0st6cZvv8HHuOc8qxoqppTJoH-rQ629yYMXZySdeeW5pZqkFxJelbrJ1RerT8FFwffhXz-1AWXImLynRlTONn0YCiYc2oGjyanZpbU8oV3y7Rzc_LthS8xZfBhARad7btkBxfw4rSuRP3b3Tw6zKXh4NPl2_95-hfgAaz1</recordid><startdate>20071206</startdate><enddate>20071206</enddate><creator>Jin, W</creator><creator>Yun, C</creator><creator>Kwak, M-K</creator><creator>Kim, T-A</creator><creator>Kim, S-J</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</general><scope>IQODW</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20071206</creationdate><title>TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling</title><author>Jin, W ; Yun, C ; Kwak, M-K ; Kim, T-A ; Kim, S-J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-e0a86242fa5a7dc85493878d5d560a0b1af307bfe5965a3d3c599385f0b8d893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Cancer</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell physiology</topic><topic>Cell receptors</topic><topic>Cell structures and functions</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cellular signal transduction</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene silencing</topic><topic>Genetic aspects</topic><topic>Growth factor receptors</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Kinases</topic><topic>Mammary gland</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Miscellaneous</topic><topic>Molecular and cellular biology</topic><topic>Neurotrophin receptors</topic><topic>NIH 3T3 Cells</topic><topic>Oncology</topic><topic>original-article</topic><topic>Phosphorylation</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Protein-tyrosine kinase</topic><topic>Receptor, trkC - antagonists & inhibitors</topic><topic>Receptor, trkC - genetics</topic><topic>Receptor, trkC - metabolism</topic><topic>Receptors, Transforming Growth Factor beta - metabolism</topic><topic>RNA, Small Interfering - pharmacology</topic><topic>Signal Transduction</topic><topic>siRNA</topic><topic>Smad2 protein</topic><topic>Smad2 Protein - metabolism</topic><topic>Smad3 Protein - metabolism</topic><topic>Transcription activation</topic><topic>Transcriptional Activation</topic><topic>Transforming Growth Factor beta - antagonists & inhibitors</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Transforming Growth Factor beta - pharmacology</topic><topic>Transforming growth factor-b</topic><topic>TrkC receptors</topic><topic>Tumor suppressor genes</topic><topic>Tumor Suppressor Proteins - antagonists & inhibitors</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Tumor Suppressor Proteins - pharmacology</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jin, W</creatorcontrib><creatorcontrib>Yun, C</creatorcontrib><creatorcontrib>Kwak, M-K</creatorcontrib><creatorcontrib>Kim, T-A</creatorcontrib><creatorcontrib>Kim, S-J</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jin, W</au><au>Yun, C</au><au>Kwak, M-K</au><au>Kim, T-A</au><au>Kim, S-J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2007-12-06</date><risdate>2007</risdate><volume>26</volume><issue>55</issue><spage>7684</spage><epage>7691</epage><pages>7684-7691</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Growing evidence suggests that overexpression of TrkC, a member of the Trk family of neurotrophin receptors, could drive tumorigenesis, invasion and metastatic capability in cancer cells. However, relatively little is known about the mechanism of TrkC-mediated oncogenesis. The TrkC gene is a partner of the Tel-TrkC (ETV6-NTRK3) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages. Recently, we have shown that ETV6-NTRK3 suppresses transforming growth factor-
β
(TGF-
β
) signaling by directly binding to the type II TGF-
β
receptor (T
β
RII). Here, we report that expression of TrkC also suppresses TGF-
β
-induced Smad2/3 phosphorylation and transcriptional activation. Silencing TrkC expression by small interfering RNA in the highly metastatic 4T1 mammary tumor cell line expressing endogenous TrkC significantly enhanced TGF-
β
-induced Smad2/3 phosphorylation and restored TGF-
β
growth inhibitory activity. In contrast, expression of TrkC in 67NR cells, in which TrkC is not expressed, suppressed TGF-
β
transcriptional activation. Moreover, we show that TrkC directly binds to the T
β
RII, thereby preventing it from interacting with the type I TGF-
β
receptor (T
β
RI). These results indicate that TrkC is an inhibitor of TGF-
β
tumor suppressor activity.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>17546043</pmid><doi>10.1038/sj.onc.1210571</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Oncogene, 2007-12, Vol.26 (55), p.7684-7691 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_69032421 |
| source | MEDLINE; Nature; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Springer Nature - Complete Springer Journals |
| subjects | Animals Apoptosis Biological and medical sciences Cancer Care and treatment Cell Biology Cell Line, Tumor Cell physiology Cell receptors Cell structures and functions Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cellular signal transduction Fundamental and applied biological sciences. Psychology Gene silencing Genetic aspects Growth factor receptors Health aspects Human Genetics Humans Internal Medicine Kinases Mammary gland Medicine Medicine & Public Health Metastases Metastasis Mice Miscellaneous Molecular and cellular biology Neurotrophin receptors NIH 3T3 Cells Oncology original-article Phosphorylation Protein-Serine-Threonine Kinases - metabolism Protein-tyrosine kinase Receptor, trkC - antagonists & inhibitors Receptor, trkC - genetics Receptor, trkC - metabolism Receptors, Transforming Growth Factor beta - metabolism RNA, Small Interfering - pharmacology Signal Transduction siRNA Smad2 protein Smad2 Protein - metabolism Smad3 Protein - metabolism Transcription activation Transcriptional Activation Transforming Growth Factor beta - antagonists & inhibitors Transforming Growth Factor beta - metabolism Transforming Growth Factor beta - pharmacology Transforming growth factor-b TrkC receptors Tumor suppressor genes Tumor Suppressor Proteins - antagonists & inhibitors Tumor Suppressor Proteins - metabolism Tumor Suppressor Proteins - pharmacology Tumorigenesis Tumors |
| title | TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling |
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