Ect2 links the PKCι-Par6α complex to Rac1 activation and cellular transformation
Protein kinase Cι (PKCι) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKCι–Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nuc...
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| Veröffentlicht in: | Oncogene 2009-10, Vol.28 (41), p.3597-3607 |
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| description | Protein kinase Cι (PKCι) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKCι–Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKCι in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKCι–Par6α complex. RNA interference-mediated knockdown of either PKCι or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKCι–Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKCι are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKCι–Par6α-Ect2 complex. |
| doi_str_mv | 10.1038/onc.2009.217 |
| format | Article |
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The mechanism by which the PKCι–Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKCι in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKCι–Par6α complex. RNA interference-mediated knockdown of either PKCι or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKCι–Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKCι are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKCι–Par6α-Ect2 complex.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2009.217</identifier><identifier>PMID: 19617897</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Apoptosis ; Cell Biology ; Cell proliferation ; Cytokinesis ; Cytoplasm ; Epithelial cells ; Extracellular signal-regulated kinase ; Genetic transformation ; Guanine ; Guanine nucleotide exchange factor ; Human Genetics ; Internal Medicine ; Kinases ; Localization ; Lung cancer ; Medicine ; Medicine & Public Health ; Non-small cell lung carcinoma ; Oncology ; original-article ; Protein kinase ; Protein kinase C ; Rac1 protein ; RNA-mediated interference ; Small cell lung carcinoma ; Tumorigenicity ; Tumors</subject><ispartof>Oncogene, 2009-10, Vol.28 (41), p.3597-3607</ispartof><rights>Macmillan Publishers Limited 2009</rights><rights>Macmillan Publishers Limited 2009.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c380t-de2db7be1b89478977850ccba5ff014ce64abd7fb93dc9a8535a3dfe7c641f2b3</citedby><cites>FETCH-LOGICAL-c380t-de2db7be1b89478977850ccba5ff014ce64abd7fb93dc9a8535a3dfe7c641f2b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,2728,27929,27930</link.rule.ids></links><search><creatorcontrib>Justilien, V</creatorcontrib><creatorcontrib>Fields, A P</creatorcontrib><title>Ect2 links the PKCι-Par6α complex to Rac1 activation and cellular transformation</title><title>Oncogene</title><addtitle>Oncogene</addtitle><description>Protein kinase Cι (PKCι) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKCι–Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKCι in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKCι–Par6α complex. RNA interference-mediated knockdown of either PKCι or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKCι–Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKCι are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKCι–Par6α-Ect2 complex.</description><subject>Apoptosis</subject><subject>Cell Biology</subject><subject>Cell proliferation</subject><subject>Cytokinesis</subject><subject>Cytoplasm</subject><subject>Epithelial cells</subject><subject>Extracellular signal-regulated kinase</subject><subject>Genetic transformation</subject><subject>Guanine</subject><subject>Guanine nucleotide exchange factor</subject><subject>Human Genetics</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Localization</subject><subject>Lung cancer</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Non-small cell lung carcinoma</subject><subject>Oncology</subject><subject>original-article</subject><subject>Protein kinase</subject><subject>Protein kinase C</subject><subject>Rac1 protein</subject><subject>RNA-mediated interference</subject><subject>Small cell lung carcinoma</subject><subject>Tumorigenicity</subject><subject>Tumors</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><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>eNp1kc1q3DAUhUVoSaZJdnkAQaGreKof25I2hTBMm5CBhpCshSzLGU9taSLJIX2sLvsS80yR46Ghha7u4n58nMMB4AyjOUaUf3ZWzwlCYk4wOwAznLMyKwqRvwMzJAqUCULJEfgQwgYhxAQih-AIixIzLtgM3C51JLBr7Y8A49rAm-vF7nd2o3y5-wW167edeYbRwVulMVQ6tk8qts5CZWuoTdcNnfIwemVD43z_-jsB7xvVBXO6v8fg_uvybnGZrb5_u1pcrDJNOYpZbUhdscrgiot8DMN4gbSuVNE0COfalLmqatZUgtZaKF7QQtG6MUyXOW5IRY_Bl8m7Hare1NrYlKOTW9_2yv-UTrXy749t1_LBPUnCSpJzmgSf9gLvHgcTouzbMJZS1rghSIIJ5rzIE_jxH3DjBm9TOUlSGMoZpzxR5xOlvQvBm-ZPFIzkOJVMU8lxqmRmCc8mPCTMPhj_Jv0PDyfeqjh489bT6pEZkRdYcKHk</recordid><startdate>20091015</startdate><enddate>20091015</enddate><creator>Justilien, V</creator><creator>Fields, A P</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><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>5PM</scope></search><sort><creationdate>20091015</creationdate><title>Ect2 links the PKCι-Par6α complex to Rac1 activation and cellular transformation</title><author>Justilien, V ; Fields, A P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-de2db7be1b89478977850ccba5ff014ce64abd7fb93dc9a8535a3dfe7c641f2b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Apoptosis</topic><topic>Cell Biology</topic><topic>Cell proliferation</topic><topic>Cytokinesis</topic><topic>Cytoplasm</topic><topic>Epithelial cells</topic><topic>Extracellular signal-regulated kinase</topic><topic>Genetic transformation</topic><topic>Guanine</topic><topic>Guanine nucleotide exchange factor</topic><topic>Human Genetics</topic><topic>Internal Medicine</topic><topic>Kinases</topic><topic>Localization</topic><topic>Lung cancer</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Non-small cell lung carcinoma</topic><topic>Oncology</topic><topic>original-article</topic><topic>Protein kinase</topic><topic>Protein kinase C</topic><topic>Rac1 protein</topic><topic>RNA-mediated interference</topic><topic>Small cell lung carcinoma</topic><topic>Tumorigenicity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Justilien, V</creatorcontrib><creatorcontrib>Fields, A P</creatorcontrib><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>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Justilien, V</au><au>Fields, A P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ect2 links the PKCι-Par6α complex to Rac1 activation and cellular transformation</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><date>2009-10-15</date><risdate>2009</risdate><volume>28</volume><issue>41</issue><spage>3597</spage><epage>3607</epage><pages>3597-3607</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Protein kinase Cι (PKCι) promotes non-small cell lung cancer (NSCLC) by binding to Par6α and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKCι–Par6α complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKCι in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKCι–Par6α complex. RNA interference-mediated knockdown of either PKCι or Par6α causes Ect2 to redistribute to the nucleus, indicating that the PKCι–Par6α complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKCι are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKCι–Par6α-Ect2 complex.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>19617897</pmid><doi>10.1038/onc.2009.217</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Cell Biology Cell proliferation Cytokinesis Cytoplasm Epithelial cells Extracellular signal-regulated kinase Genetic transformation Guanine Guanine nucleotide exchange factor Human Genetics Internal Medicine Kinases Localization Lung cancer Medicine Medicine & Public Health Non-small cell lung carcinoma Oncology original-article Protein kinase Protein kinase C Rac1 protein RNA-mediated interference Small cell lung carcinoma Tumorigenicity Tumors |
| title | Ect2 links the PKCι-Par6α complex to Rac1 activation and cellular transformation |
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