Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression
Fyn, an Src kinase family member, acts as a negative regulator of NF-E2-related factor 2 (Nrf2). Under stressful conditions, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE), activating defensive gene expression. Once Nrf2 completes activation, Fyn phosphorylate...
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| Veröffentlicht in: | The FASEB journal 2011-03, Vol.25 (3), p.1076-1087 |
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| description | Fyn, an Src kinase family member, acts as a negative regulator of NF-E2-related factor 2 (Nrf2). Under stressful conditions, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE), activating defensive gene expression. Once Nrf2 completes activation, Fyn phosphorylates tyrosine 568 of Nrf2, resulting in the nuclear export and degradation of Nrf2. The present studies demonstrate that within 0.5 h of antioxidant treatment in human hepatoblastoma (HepG2) cells, Fyn exports out of the nucleus, allowing Nrf2 unimpeded movement to the ARE. Mutation of tyrosine 213 of Fyn stymied nuclear export, suggesting that tyrosine phosphorylation controls nuclear export. Mass spectrometry confirmed tyrosine 213 as the site of phosphorylation. ChIP and real-time PCR assays revealed that FynY213A mutant caused decreased binding of Nrf2 to the promoter of defensive gene NAD(P)H:quinone oxidoreductase 1 (NQO1) and decreased NQO1 expression by 5-fold (P |
| doi_str_mv | 10.1096/fj.10-171553 |
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Under stressful conditions, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE), activating defensive gene expression. Once Nrf2 completes activation, Fyn phosphorylates tyrosine 568 of Nrf2, resulting in the nuclear export and degradation of Nrf2. The present studies demonstrate that within 0.5 h of antioxidant treatment in human hepatoblastoma (HepG2) cells, Fyn exports out of the nucleus, allowing Nrf2 unimpeded movement to the ARE. Mutation of tyrosine 213 of Fyn stymied nuclear export, suggesting that tyrosine phosphorylation controls nuclear export. Mass spectrometry confirmed tyrosine 213 as the site of phosphorylation. ChIP and real-time PCR assays revealed that FynY213A mutant caused decreased binding of Nrf2 to the promoter of defensive gene NAD(P)H:quinone oxidoreductase 1 (NQO1) and decreased NQO1 expression by 5-fold (P<0.0001) compared to wild-type Fyn. In addition, a putative nuclear export signal (NES) was identified, and mutation of it also inhibited nuclear export of Fyn. Furthermore, FynY213A caused an increased susceptibility to cell death following treatment with etoposide in mouse hepatoma (Hepa-1) cells. The preinduction regulation of Nrf2 is controlled by the nuclear export of Fyn, allowing for activation of defensive gene expression.--Kaspar, J. W., Jaiswal, A. K. Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.10-171553</identifier><identifier>PMID: 21097520</identifier><language>eng</language><publisher>United States: The Federation of American Societies for Experimental Biology</publisher><subject>Active Transport, Cell Nucleus - physiology ; Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Antioxidants - pharmacology ; Carcinoma, Hepatocellular ; Cell Death - physiology ; Cell Nucleus - metabolism ; cell survival ; Cell Survival - physiology ; cellular protection ; cytoprotective gene induction ; Cytoskeletal Proteins - metabolism ; Exportin 1 Protein ; Genistein - pharmacology ; Hep G2 Cells ; Humans ; INrf2 ; Karyopherins - antagonists & inhibitors ; Keapl ; Kelch-Like ECH-Associated Protein 1 ; Mice ; NF-E2-Related Factor 2 - metabolism ; oxidative stress ; Oxidative Stress - physiology ; Phosphorylation - physiology ; Proteasome Endopeptidase Complex - metabolism ; Proteasome Inhibitors ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins c-fyn - genetics ; Proto-Oncogene Proteins c-fyn - metabolism ; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors ; Research Communications ; Tyrosine - genetics ; Tyrosine - metabolism</subject><ispartof>The FASEB journal, 2011-03, Vol.25 (3), p.1076-1087</ispartof><rights>FASEB</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5543-fe31dcc2fe4a201c37f9985213cb3d94a6b7af67f368434e0775aef2118484973</citedby><cites>FETCH-LOGICAL-c5543-fe31dcc2fe4a201c37f9985213cb3d94a6b7af67f368434e0775aef2118484973</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.10-171553$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.10-171553$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1416,27923,27924,45573,45574</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21097520$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaspar, James W</creatorcontrib><creatorcontrib>Jaiswal, Anil K</creatorcontrib><title>Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>Fyn, an Src kinase family member, acts as a negative regulator of NF-E2-related factor 2 (Nrf2). Under stressful conditions, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE), activating defensive gene expression. Once Nrf2 completes activation, Fyn phosphorylates tyrosine 568 of Nrf2, resulting in the nuclear export and degradation of Nrf2. The present studies demonstrate that within 0.5 h of antioxidant treatment in human hepatoblastoma (HepG2) cells, Fyn exports out of the nucleus, allowing Nrf2 unimpeded movement to the ARE. Mutation of tyrosine 213 of Fyn stymied nuclear export, suggesting that tyrosine phosphorylation controls nuclear export. Mass spectrometry confirmed tyrosine 213 as the site of phosphorylation. ChIP and real-time PCR assays revealed that FynY213A mutant caused decreased binding of Nrf2 to the promoter of defensive gene NAD(P)H:quinone oxidoreductase 1 (NQO1) and decreased NQO1 expression by 5-fold (P<0.0001) compared to wild-type Fyn. In addition, a putative nuclear export signal (NES) was identified, and mutation of it also inhibited nuclear export of Fyn. Furthermore, FynY213A caused an increased susceptibility to cell death following treatment with etoposide in mouse hepatoma (Hepa-1) cells. The preinduction regulation of Nrf2 is controlled by the nuclear export of Fyn, allowing for activation of defensive gene expression.--Kaspar, J. W., Jaiswal, A. K. Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression.</description><subject>Active Transport, Cell Nucleus - physiology</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Antioxidants - pharmacology</subject><subject>Carcinoma, Hepatocellular</subject><subject>Cell Death - physiology</subject><subject>Cell Nucleus - metabolism</subject><subject>cell survival</subject><subject>Cell Survival - physiology</subject><subject>cellular protection</subject><subject>cytoprotective gene induction</subject><subject>Cytoskeletal Proteins - metabolism</subject><subject>Exportin 1 Protein</subject><subject>Genistein - pharmacology</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>INrf2</subject><subject>Karyopherins - antagonists & inhibitors</subject><subject>Keapl</subject><subject>Kelch-Like ECH-Associated Protein 1</subject><subject>Mice</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>oxidative stress</subject><subject>Oxidative Stress - physiology</subject><subject>Phosphorylation - physiology</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Proteasome Inhibitors</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins c-fyn - genetics</subject><subject>Proto-Oncogene Proteins c-fyn - metabolism</subject><subject>Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors</subject><subject>Research Communications</subject><subject>Tyrosine - genetics</subject><subject>Tyrosine - metabolism</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks9vFCEUgInR2LV686zcvHSU3zNcTLRxq6bRQ9szYdnHlg07jDDbOv99aadt9KIH8gh87wvvPRB6Tcl7SrT64Lc1NrSlUvInaEElJ43qFHmKFqTTrFGKdwfoRSlbQgglVD1HB6xmtpKRBSrnU04l9ICHy1TqylO0Y0g9dqkfc4oF93sXwWYMv4eUR5w8Xk79EbYxpuvQb_CP7Bm2bgxXc2IF3DSmIacRbk8Bb6D6a3qGUirxEj3zNhZ4dR8P0cXyy_nx1-b058m340-njZNS8MYDp2vnmAdhGaGOt17rTjLK3YqvtbBq1VqvWs9VJ7gA0rbSgmeUdqITuuWH6OPsHfarHawd1IJsNEMOO5snk2wwf9_04dJs0pXhRLCqrIJ394Kcfu2hjGYXioMYbQ9pX4xWHVVcKfZfspNCKqm1qOTRTLra95LBP76HEnM7UOO3d9u7gVb8zZ81PMIPE6xANwPXIcL0T5lZnn1my-_1Dzy4386p3iZjNzkUc3FWO80J1UKTKr8Blnu4iw</recordid><startdate>201103</startdate><enddate>201103</enddate><creator>Kaspar, James W</creator><creator>Jaiswal, Anil K</creator><general>The Federation of American Societies for Experimental Biology</general><general>Federation of American Societies for Experimental Biology</general><scope>FBQ</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>7X8</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>201103</creationdate><title>Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression</title><author>Kaspar, James W ; Jaiswal, Anil K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5543-fe31dcc2fe4a201c37f9985213cb3d94a6b7af67f368434e0775aef2118484973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Active Transport, Cell Nucleus - physiology</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Animals</topic><topic>Antioxidants - pharmacology</topic><topic>Carcinoma, Hepatocellular</topic><topic>Cell Death - physiology</topic><topic>Cell Nucleus - metabolism</topic><topic>cell survival</topic><topic>Cell Survival - physiology</topic><topic>cellular protection</topic><topic>cytoprotective gene induction</topic><topic>Cytoskeletal Proteins - metabolism</topic><topic>Exportin 1 Protein</topic><topic>Genistein - pharmacology</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>INrf2</topic><topic>Karyopherins - antagonists & inhibitors</topic><topic>Keapl</topic><topic>Kelch-Like ECH-Associated Protein 1</topic><topic>Mice</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>oxidative stress</topic><topic>Oxidative Stress - physiology</topic><topic>Phosphorylation - physiology</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Proteasome Inhibitors</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins c-fyn - genetics</topic><topic>Proto-Oncogene Proteins c-fyn - metabolism</topic><topic>Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors</topic><topic>Research Communications</topic><topic>Tyrosine - genetics</topic><topic>Tyrosine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaspar, James W</creatorcontrib><creatorcontrib>Jaiswal, Anil K</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaspar, James W</au><au>Jaiswal, Anil K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2011-03</date><risdate>2011</risdate><volume>25</volume><issue>3</issue><spage>1076</spage><epage>1087</epage><pages>1076-1087</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>Fyn, an Src kinase family member, acts as a negative regulator of NF-E2-related factor 2 (Nrf2). Under stressful conditions, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE), activating defensive gene expression. Once Nrf2 completes activation, Fyn phosphorylates tyrosine 568 of Nrf2, resulting in the nuclear export and degradation of Nrf2. The present studies demonstrate that within 0.5 h of antioxidant treatment in human hepatoblastoma (HepG2) cells, Fyn exports out of the nucleus, allowing Nrf2 unimpeded movement to the ARE. Mutation of tyrosine 213 of Fyn stymied nuclear export, suggesting that tyrosine phosphorylation controls nuclear export. Mass spectrometry confirmed tyrosine 213 as the site of phosphorylation. ChIP and real-time PCR assays revealed that FynY213A mutant caused decreased binding of Nrf2 to the promoter of defensive gene NAD(P)H:quinone oxidoreductase 1 (NQO1) and decreased NQO1 expression by 5-fold (P<0.0001) compared to wild-type Fyn. In addition, a putative nuclear export signal (NES) was identified, and mutation of it also inhibited nuclear export of Fyn. Furthermore, FynY213A caused an increased susceptibility to cell death following treatment with etoposide in mouse hepatoma (Hepa-1) cells. The preinduction regulation of Nrf2 is controlled by the nuclear export of Fyn, allowing for activation of defensive gene expression.--Kaspar, J. W., Jaiswal, A. K. Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression.</abstract><cop>United States</cop><pub>The Federation of American Societies for Experimental Biology</pub><pmid>21097520</pmid><doi>10.1096/fj.10-171553</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Active Transport, Cell Nucleus - physiology Adaptor Proteins, Signal Transducing - metabolism Animals Antioxidants - pharmacology Carcinoma, Hepatocellular Cell Death - physiology Cell Nucleus - metabolism cell survival Cell Survival - physiology cellular protection cytoprotective gene induction Cytoskeletal Proteins - metabolism Exportin 1 Protein Genistein - pharmacology Hep G2 Cells Humans INrf2 Karyopherins - antagonists & inhibitors Keapl Kelch-Like ECH-Associated Protein 1 Mice NF-E2-Related Factor 2 - metabolism oxidative stress Oxidative Stress - physiology Phosphorylation - physiology Proteasome Endopeptidase Complex - metabolism Proteasome Inhibitors Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-fyn - genetics Proto-Oncogene Proteins c-fyn - metabolism Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors Research Communications Tyrosine - genetics Tyrosine - metabolism |
| title | Tyrosine phosphorylation controls nuclear export of Fyn, allowing Nrf2 activation of cytoprotective gene expression |
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