Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2
G‐protein‐coupled receptor kinase 2 (GRK2) is a central regulator of G‐protein‐coupled receptor signaling. We report that Mdm2, an E3‐ubiquitin ligase involved in the control of cell growth and apoptosis, plays a key role in GRK2 degradation. Mdm2 and GRK2 association is enhanced by β 2 ‐adrenergic...
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| Veröffentlicht in: | The EMBO journal 2006-10, Vol.25 (20), p.4752-4762 |
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| creator | Salcedo, Alicia Mayor Jr, Federico Penela, Petronila |
| description | G‐protein‐coupled receptor kinase 2 (GRK2) is a central regulator of G‐protein‐coupled receptor signaling. We report that Mdm2, an E3‐ubiquitin ligase involved in the control of cell growth and apoptosis, plays a key role in GRK2 degradation. Mdm2 and GRK2 association is enhanced by β
2
‐adrenergic receptor stimulation and β‐arrestin. Increased Mdm2 expression accelerates GRK2 proteolysis and promotes kinase ubiquitination at defined residues, whereas GRK2 turnover is markedly impaired in Mdm2‐deficient cells. Moreover, we find that activation of the PI3K/Akt pathway by insulin‐like growth factor‐1 alters Mdm2‐mediated GRK2 degradation, leading to enhanced GRK2 stability and increased kinase levels. These data put forward a novel mechanism for controlling GRK2 expression in physiological and pathological conditions. |
| doi_str_mv | 10.1038/sj.emboj.7601351 |
| format | Article |
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2
‐adrenergic receptor stimulation and β‐arrestin. Increased Mdm2 expression accelerates GRK2 proteolysis and promotes kinase ubiquitination at defined residues, whereas GRK2 turnover is markedly impaired in Mdm2‐deficient cells. Moreover, we find that activation of the PI3K/Akt pathway by insulin‐like growth factor‐1 alters Mdm2‐mediated GRK2 degradation, leading to enhanced GRK2 stability and increased kinase levels. These data put forward a novel mechanism for controlling GRK2 expression in physiological and pathological conditions.</description><identifier>ISSN: 0261-4189</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.1038/sj.emboj.7601351</identifier><identifier>PMID: 17006543</identifier><identifier>CODEN: EMJODG</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Arrestins - metabolism ; Arrestins - pharmacology ; beta-Adrenergic Receptor Kinases - metabolism ; beta-Arrestins ; Cell Line ; Cellular biology ; degradation ; EMBO37 ; Enzymes ; G-Protein-Coupled Receptor Kinase 2 ; Gene Expression Regulation, Enzymologic - genetics ; GRK2 ; Humans ; IGF-1 ; Insulin-Like Growth Factor I - metabolism ; Insulin-Like Growth Factor I - pharmacology ; Kinases ; Mdm2 ; Oncogene Protein v-akt - metabolism ; Physiology ; Protein Processing, Post-Translational - drug effects ; Protein Processing, Post-Translational - genetics ; Proteins ; Proto-Oncogene Proteins c-mdm2 - deficiency ; Proto-Oncogene Proteins c-mdm2 - metabolism ; Signal transduction ; Signal Transduction - drug effects ; Signal Transduction - genetics ; Ubiquitin - metabolism ; Ubiquitin-Protein Ligases - metabolism</subject><ispartof>The EMBO journal, 2006-10, Vol.25 (20), p.4752-4762</ispartof><rights>European Molecular Biology Organization 2006</rights><rights>Copyright © 2006 European Molecular Biology Organization</rights><rights>Copyright Nature Publishing Group Oct 18, 2006</rights><rights>Copyright © 2006, European Molecular Biology Organization 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6171-2a542df8f4442a4fbe48efed764cb950307abab0a6047e5175f7bff79ef3a9f13</citedby><cites>FETCH-LOGICAL-c6171-2a542df8f4442a4fbe48efed764cb950307abab0a6047e5175f7bff79ef3a9f13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1618114/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1618114/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,41096,42165,45550,45551,46384,46808,51551,53766,53768</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.1038/sj.emboj.7601351$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17006543$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Salcedo, Alicia</creatorcontrib><creatorcontrib>Mayor Jr, Federico</creatorcontrib><creatorcontrib>Penela, Petronila</creatorcontrib><title>Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2</title><title>The EMBO journal</title><addtitle>EMBO J</addtitle><addtitle>EMBO J</addtitle><description>G‐protein‐coupled receptor kinase 2 (GRK2) is a central regulator of G‐protein‐coupled receptor signaling. We report that Mdm2, an E3‐ubiquitin ligase involved in the control of cell growth and apoptosis, plays a key role in GRK2 degradation. Mdm2 and GRK2 association is enhanced by β
2
‐adrenergic receptor stimulation and β‐arrestin. Increased Mdm2 expression accelerates GRK2 proteolysis and promotes kinase ubiquitination at defined residues, whereas GRK2 turnover is markedly impaired in Mdm2‐deficient cells. Moreover, we find that activation of the PI3K/Akt pathway by insulin‐like growth factor‐1 alters Mdm2‐mediated GRK2 degradation, leading to enhanced GRK2 stability and increased kinase levels. These data put forward a novel mechanism for controlling GRK2 expression in physiological and pathological conditions.</description><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Arrestins - metabolism</subject><subject>Arrestins - pharmacology</subject><subject>beta-Adrenergic Receptor Kinases - metabolism</subject><subject>beta-Arrestins</subject><subject>Cell Line</subject><subject>Cellular biology</subject><subject>degradation</subject><subject>EMBO37</subject><subject>Enzymes</subject><subject>G-Protein-Coupled Receptor Kinase 2</subject><subject>Gene Expression Regulation, Enzymologic - genetics</subject><subject>GRK2</subject><subject>Humans</subject><subject>IGF-1</subject><subject>Insulin-Like Growth Factor I - metabolism</subject><subject>Insulin-Like Growth Factor I - pharmacology</subject><subject>Kinases</subject><subject>Mdm2</subject><subject>Oncogene Protein v-akt - metabolism</subject><subject>Physiology</subject><subject>Protein Processing, Post-Translational - drug effects</subject><subject>Protein Processing, Post-Translational - genetics</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-mdm2 - deficiency</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - genetics</subject><subject>Ubiquitin - metabolism</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><issn>0261-4189</issn><issn>1460-2075</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkc1v1DAUxCMEokvhzglFHLhlsR1_xBckqMpC1YJAoD0hy0met06zdmon2_a_x5BVW5AQJ9vy_ObN02TZc4yWGJXV69gtYVv7bik4wiXDD7IFphwVBAn2MFsgwnFBcSUPsicxdgghVgn8ODvAAiHOaLnIfpy1W5LbmFu38_0O2nTJx3PIp9peTna0To_Wu1y7Nm9hE3Q7v73JV8UQ_AjWFY2fhj6hARoYRh_yi4RFyMnT7JHRfYRn-_Mw-_7--NvRh-L08-rj0dvTouFY4IJoRklrKkMpJZqaGmgFBlrBaVNLhkokdK1rpDmiAhgWzIjaGCHBlFoaXB5mb2bfYaq30DbgxqB7NQS71eFGeW3Vnz_OnquN3ynMcYUxTQav9gbBX04QR7W1sYG-1w78FBWvZErKSBK-_EvY-Sm4tJzCkhFeESaTCM2iJvgYA5jbJBipX8Wp2Knfxal9cQl5cX-DO2DfVBLIWXBle7j5r6E6Pnt3cmeOZzYmzG0g3Av970DFzNg4wvXtPB0uFBelYGr9aaW-rk_k-kspFSt_AnViyPI</recordid><startdate>20061018</startdate><enddate>20061018</enddate><creator>Salcedo, Alicia</creator><creator>Mayor Jr, Federico</creator><creator>Penela, Petronila</creator><general>John Wiley & Sons, Ltd</general><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><scope>BSCLL</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</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>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</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>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PCBAR</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20061018</creationdate><title>Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2</title><author>Salcedo, Alicia ; Mayor Jr, Federico ; Penela, Petronila</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6171-2a542df8f4442a4fbe48efed764cb950307abab0a6047e5175f7bff79ef3a9f13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Arrestins - metabolism</topic><topic>Arrestins - pharmacology</topic><topic>beta-Adrenergic Receptor Kinases - metabolism</topic><topic>beta-Arrestins</topic><topic>Cell Line</topic><topic>Cellular biology</topic><topic>degradation</topic><topic>EMBO37</topic><topic>Enzymes</topic><topic>G-Protein-Coupled Receptor Kinase 2</topic><topic>Gene Expression Regulation, Enzymologic - genetics</topic><topic>GRK2</topic><topic>Humans</topic><topic>IGF-1</topic><topic>Insulin-Like Growth Factor I - metabolism</topic><topic>Insulin-Like Growth Factor I - pharmacology</topic><topic>Kinases</topic><topic>Mdm2</topic><topic>Oncogene Protein v-akt - metabolism</topic><topic>Physiology</topic><topic>Protein Processing, Post-Translational - drug effects</topic><topic>Protein Processing, Post-Translational - genetics</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-mdm2 - deficiency</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - genetics</topic><topic>Ubiquitin - metabolism</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Salcedo, Alicia</creatorcontrib><creatorcontrib>Mayor Jr, Federico</creatorcontrib><creatorcontrib>Penela, Petronila</creatorcontrib><collection>Istex</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>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest 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>ProQuest 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)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>Earth, Atmospheric & Aquatic Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</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>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Research Library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Earth, Atmospheric & Aquatic Science Database</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 Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The EMBO journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Salcedo, Alicia</au><au>Mayor Jr, Federico</au><au>Penela, Petronila</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2</atitle><jtitle>The EMBO journal</jtitle><stitle>EMBO J</stitle><addtitle>EMBO J</addtitle><date>2006-10-18</date><risdate>2006</risdate><volume>25</volume><issue>20</issue><spage>4752</spage><epage>4762</epage><pages>4752-4762</pages><issn>0261-4189</issn><eissn>1460-2075</eissn><coden>EMJODG</coden><abstract>G‐protein‐coupled receptor kinase 2 (GRK2) is a central regulator of G‐protein‐coupled receptor signaling. We report that Mdm2, an E3‐ubiquitin ligase involved in the control of cell growth and apoptosis, plays a key role in GRK2 degradation. Mdm2 and GRK2 association is enhanced by β
2
‐adrenergic receptor stimulation and β‐arrestin. Increased Mdm2 expression accelerates GRK2 proteolysis and promotes kinase ubiquitination at defined residues, whereas GRK2 turnover is markedly impaired in Mdm2‐deficient cells. Moreover, we find that activation of the PI3K/Akt pathway by insulin‐like growth factor‐1 alters Mdm2‐mediated GRK2 degradation, leading to enhanced GRK2 stability and increased kinase levels. These data put forward a novel mechanism for controlling GRK2 expression in physiological and pathological conditions.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>17006543</pmid><doi>10.1038/sj.emboj.7601351</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Apoptosis - drug effects Apoptosis - genetics Arrestins - metabolism Arrestins - pharmacology beta-Adrenergic Receptor Kinases - metabolism beta-Arrestins Cell Line Cellular biology degradation EMBO37 Enzymes G-Protein-Coupled Receptor Kinase 2 Gene Expression Regulation, Enzymologic - genetics GRK2 Humans IGF-1 Insulin-Like Growth Factor I - metabolism Insulin-Like Growth Factor I - pharmacology Kinases Mdm2 Oncogene Protein v-akt - metabolism Physiology Protein Processing, Post-Translational - drug effects Protein Processing, Post-Translational - genetics Proteins Proto-Oncogene Proteins c-mdm2 - deficiency Proto-Oncogene Proteins c-mdm2 - metabolism Signal transduction Signal Transduction - drug effects Signal Transduction - genetics Ubiquitin - metabolism Ubiquitin-Protein Ligases - metabolism |
| title | Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2 |
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