The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways
Cyclic adenosine 3′, 5′-monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP-dependent protein kinases (PKAs) 1 , 2 but also activates certain ion channels and guanine nucleotide exchange factors (Epacs) 3 . Metabolism of c...
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| Veröffentlicht in: | Nature (London) 2005-09, Vol.437 (7058), p.574-578 |
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| creator | Dodge-Kafka, Kimberly L. Soughayer, Joseph Pare, Genevieve C. Carlisle Michel, Jennifer J. Langeberg, Lorene K. Kapiloff, Michael S. Scott, John D. |
| description | Cyclic adenosine 3′, 5′-monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP-dependent protein kinases (PKAs)
1
,
2
but also activates certain ion channels and guanine nucleotide exchange factors (Epacs)
3
. Metabolism of cAMP is catalysed by phosphodiesterases (PDEs)
4
,
5
. Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated. |
| doi_str_mv | 10.1038/nature03966 |
| format | Article |
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,
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but also activates certain ion channels and guanine nucleotide exchange factors (Epacs)
3
. Metabolism of cAMP is catalysed by phosphodiesterases (PDEs)
4
,
5
. Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature03966</identifier><identifier>PMID: 16177794</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>3',5'-Cyclic-AMP Phosphodiesterases - genetics ; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism ; Adapter proteins ; Adenosine ; Animals ; Biological and medical sciences ; Cell Line ; Cell physiology ; Cellular biology ; Cyclic AMP - metabolism ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Cytokines - metabolism ; Fundamental and applied biological sciences. Psychology ; Guanine Nucleotide Exchange Factors - metabolism ; Humanities and Social Sciences ; Humans ; Hypertrophy - chemically induced ; letter ; Mitogen-Activated Protein Kinase 7 - metabolism ; Molecular and cellular biology ; Molecular biology ; multidisciplinary ; Multiprotein Complexes - chemistry ; Multiprotein Complexes - genetics ; Multiprotein Complexes - metabolism ; Myocardium - metabolism ; Myocardium - pathology ; Rats ; Science ; Science (multidisciplinary) ; Signal Transduction</subject><ispartof>Nature (London), 2005-09, Vol.437 (7058), p.574-578</ispartof><rights>Springer Nature Limited 2005</rights><rights>2006 INIST-CNRS</rights><rights>COPYRIGHT 2005 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 22, 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c653t-9e952b295953034c77c9df068ed131f22b6e894c6fcaba423387565fc5ad28373</citedby><cites>FETCH-LOGICAL-c653t-9e952b295953034c77c9df068ed131f22b6e894c6fcaba423387565fc5ad28373</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/nature03966$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature03966$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17124122$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16177794$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dodge-Kafka, Kimberly L.</creatorcontrib><creatorcontrib>Soughayer, Joseph</creatorcontrib><creatorcontrib>Pare, Genevieve C.</creatorcontrib><creatorcontrib>Carlisle Michel, Jennifer J.</creatorcontrib><creatorcontrib>Langeberg, Lorene K.</creatorcontrib><creatorcontrib>Kapiloff, Michael S.</creatorcontrib><creatorcontrib>Scott, John D.</creatorcontrib><title>The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Cyclic adenosine 3′, 5′-monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP-dependent protein kinases (PKAs)
1
,
2
but also activates certain ion channels and guanine nucleotide exchange factors (Epacs)
3
. Metabolism of cAMP is catalysed by phosphodiesterases (PDEs)
4
,
5
. Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated.</description><subject>3',5'-Cyclic-AMP Phosphodiesterases - genetics</subject><subject>3',5'-Cyclic-AMP Phosphodiesterases - metabolism</subject><subject>Adapter proteins</subject><subject>Adenosine</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cell physiology</subject><subject>Cellular biology</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 4</subject><subject>Cytokines - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Guanine Nucleotide Exchange Factors - metabolism</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Hypertrophy - chemically induced</subject><subject>letter</subject><subject>Mitogen-Activated Protein Kinase 7 - metabolism</subject><subject>Molecular and cellular biology</subject><subject>Molecular biology</subject><subject>multidisciplinary</subject><subject>Multiprotein Complexes - chemistry</subject><subject>Multiprotein Complexes - genetics</subject><subject>Multiprotein Complexes - metabolism</subject><subject>Myocardium - metabolism</subject><subject>Myocardium - pathology</subject><subject>Rats</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal Transduction</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqF0ltv0zAYBmALgVgpXHGPIqQhIcjwIT7kMpoGTAwxwbglcp0vrUdqd7ajbf8eV63oiiohX1iOH3_x4UXoJcEnBDP1wek0BsCsFuIRmpBKirISSj5GE4ypKrFi4gg9i_EaY8yJrJ6iIyKIlLKuJujX1QKKVfAJrCt-W6cjFE2hnVn4YN3879Sy-dJcFsb70GWUIBbp1hfWJZiHPOwK03y9LKDvwSQfipVOi1t9H5-jJ70eIrzY9lP08-PZ1enn8uLbp_PT5qI0grNU1lBzOqM1rznDrDJSmrrrsVDQEUZ6SmcCVF0Z0Rs90xVlTEkueG-47qhikk3Rm03dvN-bEWJqlzYaGAbtwI-xFUoQTpT6LySSK7XexBS9_gde-zG4fIiW4opLwliVUblBcz1Aa13vU9BmDg6CHryD3ubPDVE8P0g-2q7onjcre9M-RCcHUG4dLK05WPXt3oJsEtyluR5jbM9_fN-37zbWBB9jgL5dBbvU4b4luF3HqX0Qp6xfbS9hnC2h29ltfjI43gIdjR76kJNj485JQitCaXbvNy6u1rGCsLvNQ__9A3Cf3pg</recordid><startdate>20050922</startdate><enddate>20050922</enddate><creator>Dodge-Kafka, Kimberly L.</creator><creator>Soughayer, Joseph</creator><creator>Pare, Genevieve C.</creator><creator>Carlisle Michel, Jennifer J.</creator><creator>Langeberg, Lorene K.</creator><creator>Kapiloff, Michael S.</creator><creator>Scott, John D.</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</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>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>7X8</scope></search><sort><creationdate>20050922</creationdate><title>The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways</title><author>Dodge-Kafka, Kimberly L. ; 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Psychology</topic><topic>Guanine Nucleotide Exchange Factors - metabolism</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Hypertrophy - chemically induced</topic><topic>letter</topic><topic>Mitogen-Activated Protein Kinase 7 - metabolism</topic><topic>Molecular and cellular biology</topic><topic>Molecular biology</topic><topic>multidisciplinary</topic><topic>Multiprotein Complexes - chemistry</topic><topic>Multiprotein Complexes - genetics</topic><topic>Multiprotein Complexes - metabolism</topic><topic>Myocardium - metabolism</topic><topic>Myocardium - pathology</topic><topic>Rats</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dodge-Kafka, Kimberly L.</creatorcontrib><creatorcontrib>Soughayer, Joseph</creatorcontrib><creatorcontrib>Pare, Genevieve C.</creatorcontrib><creatorcontrib>Carlisle Michel, Jennifer J.</creatorcontrib><creatorcontrib>Langeberg, Lorene K.</creatorcontrib><creatorcontrib>Kapiloff, Michael S.</creatorcontrib><creatorcontrib>Scott, John D.</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>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Environment Abstracts</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical 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>Agricultural Science Collection</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>Psychology Database (Alumni)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>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 Materials Science Collection</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>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dodge-Kafka, Kimberly L.</au><au>Soughayer, Joseph</au><au>Pare, Genevieve C.</au><au>Carlisle Michel, Jennifer J.</au><au>Langeberg, Lorene K.</au><au>Kapiloff, Michael S.</au><au>Scott, John D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2005-09-22</date><risdate>2005</risdate><volume>437</volume><issue>7058</issue><spage>574</spage><epage>578</epage><pages>574-578</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>Cyclic adenosine 3′, 5′-monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP-dependent protein kinases (PKAs)
1
,
2
but also activates certain ion channels and guanine nucleotide exchange factors (Epacs)
3
. Metabolism of cAMP is catalysed by phosphodiesterases (PDEs)
4
,
5
. Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>16177794</pmid><doi>10.1038/nature03966</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature (London), 2005-09, Vol.437 (7058), p.574-578 |
| issn | 0028-0836 1476-4687 |
| language | eng |
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| source | MEDLINE; Nature; SpringerLink Journals - AutoHoldings |
| subjects | 3',5'-Cyclic-AMP Phosphodiesterases - genetics 3',5'-Cyclic-AMP Phosphodiesterases - metabolism Adapter proteins Adenosine Animals Biological and medical sciences Cell Line Cell physiology Cellular biology Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism Cyclic Nucleotide Phosphodiesterases, Type 4 Cytokines - metabolism Fundamental and applied biological sciences. Psychology Guanine Nucleotide Exchange Factors - metabolism Humanities and Social Sciences Humans Hypertrophy - chemically induced letter Mitogen-Activated Protein Kinase 7 - metabolism Molecular and cellular biology Molecular biology multidisciplinary Multiprotein Complexes - chemistry Multiprotein Complexes - genetics Multiprotein Complexes - metabolism Myocardium - metabolism Myocardium - pathology Rats Science Science (multidisciplinary) Signal Transduction |
| title | The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways |
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