A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK
Retinoic acid (RA) regulates several gene programs by nuclear RA receptors (RARs) that are ligand-dependent transcriptional transregulators. The basic mechanism for switching on transcription of cognate-target genes involves RAR binding at specific response elements and a network of interactions wit...
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| Veröffentlicht in: | Oncogene 2012-07, Vol.31 (28), p.3333-3345 |
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| description | Retinoic acid (RA) regulates several gene programs by nuclear RA receptors (RARs) that are ligand-dependent transcriptional transregulators. The basic mechanism for switching on transcription of cognate-target genes involves RAR binding at specific response elements and a network of interactions with coregulatory protein complexes. In addition to these classical genomic effects, we recently demonstrated that RA also induces the rapid activation of the p38MAPK/MSK1 pathway, with characteristic downstream consequences on the phosphorylation of RARs and the expression of their target genes. Here, we aimed at deciphering the underlying mechanism of the rapid non-genomic effects of RA. We highlighted a novel paradigm in which a fraction of the cellular RARα pool is present in membrane lipid rafts, where it forms complexes with G protein alpha Q (Gαq) in response to RA. This rapid RA-induced formation of RARα/Gαq complexes in lipid rafts is required for the activation of p38MAPK that occurs in response to RA. Accordingly, in RA-resistant cancer cells, characterized by the absence of p38MAPK activation, RARα present in membrane lipid rafts does not associate with Gαq, pointing out the essential contribution of RARα/Gαq complexes in RA signaling. |
| doi_str_mv | 10.1038/onc.2011.499 |
| format | Article |
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The basic mechanism for switching on transcription of cognate-target genes involves RAR binding at specific response elements and a network of interactions with coregulatory protein complexes. In addition to these classical genomic effects, we recently demonstrated that RA also induces the rapid activation of the p38MAPK/MSK1 pathway, with characteristic downstream consequences on the phosphorylation of RARs and the expression of their target genes. Here, we aimed at deciphering the underlying mechanism of the rapid non-genomic effects of RA. We highlighted a novel paradigm in which a fraction of the cellular RARα pool is present in membrane lipid rafts, where it forms complexes with G protein alpha Q (Gαq) in response to RA. This rapid RA-induced formation of RARα/Gαq complexes in lipid rafts is required for the activation of p38MAPK that occurs in response to RA. Accordingly, in RA-resistant cancer cells, characterized by the absence of p38MAPK activation, RARα present in membrane lipid rafts does not associate with Gαq, pointing out the essential contribution of RARα/Gαq complexes in RA signaling.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2011.499</identifier><identifier>PMID: 22056876</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Apoptosis ; Cancer ; Cell Biology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cellular signal transduction ; Enzyme Activation - drug effects ; G proteins ; Genetic aspects ; Genomics ; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism ; Guanine nucleotide-binding protein ; Human Genetics ; Humans ; Internal Medicine ; Lipid rafts ; Lipids ; Medicine ; Medicine & Public Health ; Membrane Microdomains - drug effects ; Membrane Microdomains - metabolism ; Mitogen-activated protein kinases ; Oncology ; original-article ; p38 Mitogen-Activated Protein Kinases - metabolism ; Phosphorylation ; Physiological aspects ; Protein Binding - drug effects ; Protein Transport - drug effects ; Proteins ; Receptor, ErbB-2 - metabolism ; Receptors, Retinoic Acid - metabolism ; Regulatory sequences ; Retinoic Acid Receptor alpha ; Retinoic acid receptors ; Signal transduction ; Signal Transduction - drug effects ; Transcription ; Tretinoin ; Tretinoin - pharmacology</subject><ispartof>Oncogene, 2012-07, Vol.31 (28), p.3333-3345</ispartof><rights>Macmillan Publishers Limited 2012</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Macmillan Publishers Limited 2012.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c495t-e26631e27f44a6eaa8246edc445f57279b228f8f5b24c7942caaa6326ce90cbf3</citedby><cites>FETCH-LOGICAL-c495t-e26631e27f44a6eaa8246edc445f57279b228f8f5b24c7942caaa6326ce90cbf3</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/onc.2011.499$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2011.499$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22056876$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Piskunov, A</creatorcontrib><creatorcontrib>Rochette-Egly, C</creatorcontrib><title>A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Retinoic acid (RA) regulates several gene programs by nuclear RA receptors (RARs) that are ligand-dependent transcriptional transregulators. The basic mechanism for switching on transcription of cognate-target genes involves RAR binding at specific response elements and a network of interactions with coregulatory protein complexes. In addition to these classical genomic effects, we recently demonstrated that RA also induces the rapid activation of the p38MAPK/MSK1 pathway, with characteristic downstream consequences on the phosphorylation of RARs and the expression of their target genes. Here, we aimed at deciphering the underlying mechanism of the rapid non-genomic effects of RA. We highlighted a novel paradigm in which a fraction of the cellular RARα pool is present in membrane lipid rafts, where it forms complexes with G protein alpha Q (Gαq) in response to RA. This rapid RA-induced formation of RARα/Gαq complexes in lipid rafts is required for the activation of p38MAPK that occurs in response to RA. Accordingly, in RA-resistant cancer cells, characterized by the absence of p38MAPK activation, RARα present in membrane lipid rafts does not associate with Gαq, pointing out the essential contribution of RARα/Gαq complexes in RA signaling.</description><subject>Apoptosis</subject><subject>Cancer</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cellular signal transduction</subject><subject>Enzyme Activation - drug effects</subject><subject>G proteins</subject><subject>Genetic aspects</subject><subject>Genomics</subject><subject>GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism</subject><subject>Guanine nucleotide-binding protein</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Lipid rafts</subject><subject>Lipids</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane Microdomains - drug effects</subject><subject>Membrane Microdomains - metabolism</subject><subject>Mitogen-activated protein kinases</subject><subject>Oncology</subject><subject>original-article</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Protein Binding - drug effects</subject><subject>Protein Transport - drug effects</subject><subject>Proteins</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>Receptors, Retinoic Acid - metabolism</subject><subject>Regulatory sequences</subject><subject>Retinoic Acid Receptor alpha</subject><subject>Retinoic acid receptors</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Transcription</subject><subject>Tretinoin</subject><subject>Tretinoin - pharmacology</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</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>eNqNkk1vFSEYhYnR2Gt159qQuHHhXIHhY1hOmlqNNWqja8JwXyrNzDAC169_1T_S3yQ3t9poujAsCPCck_OGg9BjStaUtN2LOLs1I5SuudZ30IpyJRshNL-LVkQL0mjWsgP0IOcLQojShN1HB4wRITslV-hnjxOUMMfgsHVhU08OlhITPuvPri7xEuOIlwQZ5oLDjCeYhmRnwGNYdrT1JWMf05Sxi9MywnfI-Fson_FJlcUCVXN1-QGXWO1L-GoL4KXt3vbv3zxE97wdMzy63g_Rp5fHH49eNafvTl4f9aeN41qUBpiULQWmPOdWgrUd4xI2jnPhhWJKD4x1vvNiYNwpzZmz1sqWSQeauMG3h-jZ3rfm-bKFXMwUsoNxrGPEbTaUsI60ilP6PyjXrdBaVPTpP-hF3Ka5DmKY5FSQtqXqhjq3I5gw-1iSdTtT0zOtOFP1Syq1voWqawNTcHEGH-r9X4Lne4FLMecE3iwpTDb9qAnNrhWmtsLsWmFqKyr-5Drrdphg8wf-XYMKNHsg16f5HNLNMLca_gIxOMBI</recordid><startdate>20120712</startdate><enddate>20120712</enddate><creator>Piskunov, A</creator><creator>Rochette-Egly, C</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><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>20120712</creationdate><title>A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK</title><author>Piskunov, A ; Rochette-Egly, C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c495t-e26631e27f44a6eaa8246edc445f57279b228f8f5b24c7942caaa6326ce90cbf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Apoptosis</topic><topic>Cancer</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cellular signal transduction</topic><topic>Enzyme Activation - drug effects</topic><topic>G proteins</topic><topic>Genetic aspects</topic><topic>Genomics</topic><topic>GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism</topic><topic>Guanine nucleotide-binding protein</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Lipid rafts</topic><topic>Lipids</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Membrane Microdomains - drug effects</topic><topic>Membrane Microdomains - metabolism</topic><topic>Mitogen-activated protein kinases</topic><topic>Oncology</topic><topic>original-article</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Protein Binding - drug effects</topic><topic>Protein Transport - drug effects</topic><topic>Proteins</topic><topic>Receptor, ErbB-2 - metabolism</topic><topic>Receptors, Retinoic Acid - metabolism</topic><topic>Regulatory sequences</topic><topic>Retinoic Acid Receptor alpha</topic><topic>Retinoic acid receptors</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Transcription</topic><topic>Tretinoin</topic><topic>Tretinoin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Piskunov, A</creatorcontrib><creatorcontrib>Rochette-Egly, C</creatorcontrib><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>Piskunov, A</au><au>Rochette-Egly, C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2012-07-12</date><risdate>2012</risdate><volume>31</volume><issue>28</issue><spage>3333</spage><epage>3345</epage><pages>3333-3345</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Retinoic acid (RA) regulates several gene programs by nuclear RA receptors (RARs) that are ligand-dependent transcriptional transregulators. The basic mechanism for switching on transcription of cognate-target genes involves RAR binding at specific response elements and a network of interactions with coregulatory protein complexes. In addition to these classical genomic effects, we recently demonstrated that RA also induces the rapid activation of the p38MAPK/MSK1 pathway, with characteristic downstream consequences on the phosphorylation of RARs and the expression of their target genes. Here, we aimed at deciphering the underlying mechanism of the rapid non-genomic effects of RA. We highlighted a novel paradigm in which a fraction of the cellular RARα pool is present in membrane lipid rafts, where it forms complexes with G protein alpha Q (Gαq) in response to RA. This rapid RA-induced formation of RARα/Gαq complexes in lipid rafts is required for the activation of p38MAPK that occurs in response to RA. Accordingly, in RA-resistant cancer cells, characterized by the absence of p38MAPK activation, RARα present in membrane lipid rafts does not associate with Gαq, pointing out the essential contribution of RARα/Gαq complexes in RA signaling.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22056876</pmid><doi>10.1038/onc.2011.499</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Cancer Cell Biology Cell Line, Tumor Cell Proliferation - drug effects Cellular signal transduction Enzyme Activation - drug effects G proteins Genetic aspects Genomics GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism Guanine nucleotide-binding protein Human Genetics Humans Internal Medicine Lipid rafts Lipids Medicine Medicine & Public Health Membrane Microdomains - drug effects Membrane Microdomains - metabolism Mitogen-activated protein kinases Oncology original-article p38 Mitogen-Activated Protein Kinases - metabolism Phosphorylation Physiological aspects Protein Binding - drug effects Protein Transport - drug effects Proteins Receptor, ErbB-2 - metabolism Receptors, Retinoic Acid - metabolism Regulatory sequences Retinoic Acid Receptor alpha Retinoic acid receptors Signal transduction Signal Transduction - drug effects Transcription Tretinoin Tretinoin - pharmacology |
| title | A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK |
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