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Isoform-specific regulation of Akt by PDGF-induced reactive oxygen species
Isoform-specific signaling of Akt, a major signaling hub and a prominent therapeutic target, remained poorly defined until recently. Subcellular distribution, tissue-specific expression, substrate specificity, and posttranslational modifications are believed to underlie isoform-specific signaling of...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS 2011-06, Vol.108 (26), p.10550-10555 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Wani, Revati Qian, Jiang Yin, Leimiao Bechtold, Erika King, S. Bruce Poole, Leslie B Paek, Eunok Tsang, Allen W Furdui, Cristina M |
| description | Isoform-specific signaling of Akt, a major signaling hub and a prominent therapeutic target, remained poorly defined until recently. Subcellular distribution, tissue-specific expression, substrate specificity, and posttranslational modifications are believed to underlie isoform-specific signaling of Akt. The studies reported here show inhibition of Akt2 activity under physiologically relevant conditions of oxidation created by PDGF-induced reactive oxygen species. Combined MS and functional assays identified Cys124 located in the linker region between the N-terminal pleckstrin homology domain and the catalytic kinase domain as one of the unique regulatory redox sites in Akt2 with functional consequence on PDGF-stimulated glucose uptake. A model is proposed describing the consequence of increased endogenous oxidation induced by extracellular cues such as PDGF on Akt2 activity. |
| doi_str_mv | 10.1073/pnas.1011665108 |
| format | article |
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Bruce ; Poole, Leslie B ; Paek, Eunok ; Tsang, Allen W ; Furdui, Cristina M</creator><creatorcontrib>Wani, Revati ; Qian, Jiang ; Yin, Leimiao ; Bechtold, Erika ; King, S. Bruce ; Poole, Leslie B ; Paek, Eunok ; Tsang, Allen W ; Furdui, Cristina M</creatorcontrib><description>Isoform-specific signaling of Akt, a major signaling hub and a prominent therapeutic target, remained poorly defined until recently. Subcellular distribution, tissue-specific expression, substrate specificity, and posttranslational modifications are believed to underlie isoform-specific signaling of Akt. The studies reported here show inhibition of Akt2 activity under physiologically relevant conditions of oxidation created by PDGF-induced reactive oxygen species. Combined MS and functional assays identified Cys124 located in the linker region between the N-terminal pleckstrin homology domain and the catalytic kinase domain as one of the unique regulatory redox sites in Akt2 with functional consequence on PDGF-stimulated glucose uptake. A model is proposed describing the consequence of increased endogenous oxidation induced by extracellular cues such as PDGF on Akt2 activity.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1011665108</identifier><identifier>PMID: 21670275</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>3T3 cells ; active sites ; Amino Acid Sequence ; Animals ; Base Sequence ; Biological Sciences ; Cell Line ; Cells ; Disulfides ; DNA Primers ; Glucose ; Humans ; Insulin ; Kinases ; Mice ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; NIH 3T3 Cells ; Oxidation ; Oxidation-Reduction ; Phospholipase C gamma - metabolism ; Phosphorylation ; Physiological regulation ; Platelet-Derived Growth Factor - metabolism ; pleckstrin ; post-translational modification ; Protein isoforms ; Protein Isoforms - metabolism ; Proto-Oncogene Proteins c-akt - chemistry ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; sequence homology ; Signal Transduction ; Signaling proteins ; substrate specificity ; Tissues</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-06, Vol.108 (26), p.10550-10555</ispartof><rights>copyright © 1993–2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jun 28, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c556t-89fb6ecfa6eb0a01435d2f1be0b3cfa901945563ae1fa633b76f4ddc393e17393</citedby><cites>FETCH-LOGICAL-c556t-89fb6ecfa6eb0a01435d2f1be0b3cfa901945563ae1fa633b76f4ddc393e17393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/26.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27978651$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27978651$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,58238,58471</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21670275$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wani, Revati</creatorcontrib><creatorcontrib>Qian, Jiang</creatorcontrib><creatorcontrib>Yin, Leimiao</creatorcontrib><creatorcontrib>Bechtold, Erika</creatorcontrib><creatorcontrib>King, S. Bruce</creatorcontrib><creatorcontrib>Poole, Leslie B</creatorcontrib><creatorcontrib>Paek, Eunok</creatorcontrib><creatorcontrib>Tsang, Allen W</creatorcontrib><creatorcontrib>Furdui, Cristina M</creatorcontrib><title>Isoform-specific regulation of Akt by PDGF-induced reactive oxygen species</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Isoform-specific signaling of Akt, a major signaling hub and a prominent therapeutic target, remained poorly defined until recently. Subcellular distribution, tissue-specific expression, substrate specificity, and posttranslational modifications are believed to underlie isoform-specific signaling of Akt. The studies reported here show inhibition of Akt2 activity under physiologically relevant conditions of oxidation created by PDGF-induced reactive oxygen species. 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A model is proposed describing the consequence of increased endogenous oxidation induced by extracellular cues such as PDGF on Akt2 activity.</description><subject>3T3 cells</subject><subject>active sites</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Biological Sciences</subject><subject>Cell Line</subject><subject>Cells</subject><subject>Disulfides</subject><subject>DNA Primers</subject><subject>Glucose</subject><subject>Humans</subject><subject>Insulin</subject><subject>Kinases</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Mutagenesis, Site-Directed</subject><subject>NIH 3T3 Cells</subject><subject>Oxidation</subject><subject>Oxidation-Reduction</subject><subject>Phospholipase C gamma - metabolism</subject><subject>Phosphorylation</subject><subject>Physiological regulation</subject><subject>Platelet-Derived Growth Factor - metabolism</subject><subject>pleckstrin</subject><subject>post-translational modification</subject><subject>Protein isoforms</subject><subject>Protein Isoforms - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - chemistry</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>sequence homology</subject><subject>Signal Transduction</subject><subject>Signaling proteins</subject><subject>substrate specificity</subject><subject>Tissues</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNpVkM1vEzEQxS0EomngzAlYcV86s_5aX5CqQktRJZCgZ8vrtYNDsk7t3Yr893VIaODiseb95s3oEfIK4T2CpGebweTyQxSCI7RPyAxBYS2YgqdkBtDIumUNOyGnOS8BQPEWnpOTBoUsGp-RL9c5-pjWdd44G3ywVXKLaWXGEIcq-ur811h12-rbx6vLOgz9ZF1fCGPHcO-q-Hu7cEP1Z9TlF-SZN6vsXh7qnNxefvpx8bm--Xp1fXF-U1vOxVi3ynfCWW-E68AAMsr7xmPnoKOlqwAVKyA1DgtDaSeFZ31vqaIOZXnn5MPedzN1a9dbN4zJrPQmhbVJWx1N0P8rQ_ipF_FeU2ykoqIYvDsYpHg3uTzqZZzSUG7WrWRMcVainZOzPWRTzDk5_7gAQe-y17vs9TH7MvHm37se-b9hF6A6ALvJo12rG1EK51CQ13tkmceYjhZSybZsKfrbve5N1GaRQta33xtAASU2FJzRB4fwnhU</recordid><startdate>20110628</startdate><enddate>20110628</enddate><creator>Wani, Revati</creator><creator>Qian, Jiang</creator><creator>Yin, Leimiao</creator><creator>Bechtold, Erika</creator><creator>King, S. 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The studies reported here show inhibition of Akt2 activity under physiologically relevant conditions of oxidation created by PDGF-induced reactive oxygen species. Combined MS and functional assays identified Cys124 located in the linker region between the N-terminal pleckstrin homology domain and the catalytic kinase domain as one of the unique regulatory redox sites in Akt2 with functional consequence on PDGF-stimulated glucose uptake. A model is proposed describing the consequence of increased endogenous oxidation induced by extracellular cues such as PDGF on Akt2 activity.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21670275</pmid><doi>10.1073/pnas.1011665108</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3T3 cells active sites Amino Acid Sequence Animals Base Sequence Biological Sciences Cell Line Cells Disulfides DNA Primers Glucose Humans Insulin Kinases Mice Molecular Sequence Data Mutagenesis, Site-Directed NIH 3T3 Cells Oxidation Oxidation-Reduction Phospholipase C gamma - metabolism Phosphorylation Physiological regulation Platelet-Derived Growth Factor - metabolism pleckstrin post-translational modification Protein isoforms Protein Isoforms - metabolism Proto-Oncogene Proteins c-akt - chemistry Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Reactive oxygen species Reactive Oxygen Species - metabolism sequence homology Signal Transduction Signaling proteins substrate specificity Tissues |
| title | Isoform-specific regulation of Akt by PDGF-induced reactive oxygen species |
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