Itch E3 Ligase-Mediated Regulation of TGF-β Signaling by Modulating Smad2 Phosphorylation
Protein ubiquitination has been implicated in the intracellular biochemical events transduced by TGF-β receptor via different mechanisms including the degradation of Smads or their binding proteins. Here we show that loss of Itch E3 ligase in mouse embryonic fibroblasts (MEFs) results in reduced sus...
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| Veröffentlicht in: | Molecular cell 2004-09, Vol.15 (5), p.825-831 |
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| creator | Bai, Yongli Yang, Chun Hu, Kathrin Elly, Chris Liu, Yun-Cai |
| description | Protein ubiquitination has been implicated in the intracellular biochemical events transduced by TGF-β receptor via different mechanisms including the degradation of Smads or their binding proteins. Here we show that loss of Itch E3 ligase in mouse embryonic fibroblasts (MEFs) results in reduced susceptibility of TGF-β-induced cell growth arrest and decreased phosphorylation of Smad2, without apparent alteration in protein levels for Smad2, Smad4, and Smad7 in Itch−/− MEFs. Itch promotes ubiquitination of Smad2 and augments Smad2 phosphorylation that requires an intact ligase activity of Itch. Moreover, Itch facilitates complex formation between TGF-β receptor and Smad2 and enhances TGF-β-induced transcription. This study reveals a previously unrecognized positive TGF-β signaling pathway via proteolysis-independent ubiquitination. |
| doi_str_mv | 10.1016/j.molcel.2004.07.021 |
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Here we show that loss of Itch E3 ligase in mouse embryonic fibroblasts (MEFs) results in reduced susceptibility of TGF-β-induced cell growth arrest and decreased phosphorylation of Smad2, without apparent alteration in protein levels for Smad2, Smad4, and Smad7 in Itch−/− MEFs. Itch promotes ubiquitination of Smad2 and augments Smad2 phosphorylation that requires an intact ligase activity of Itch. Moreover, Itch facilitates complex formation between TGF-β receptor and Smad2 and enhances TGF-β-induced transcription. This study reveals a previously unrecognized positive TGF-β signaling pathway via proteolysis-independent ubiquitination.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2004.07.021</identifier><identifier>PMID: 15350225</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cell Division - drug effects ; Cell Division - genetics ; Cells, Cultured ; DNA-Binding Proteins - metabolism ; Female ; Fetus ; Fibroblasts - metabolism ; Male ; Mice ; Mice, Knockout ; Phosphorylation ; Receptors, Transforming Growth Factor beta - metabolism ; Signal Transduction - physiology ; Smad2 Protein ; Trans-Activators - metabolism ; Transcription, Genetic - genetics ; Transforming Growth Factor beta - biosynthesis ; Transforming Growth Factor beta - genetics ; Transforming Growth Factor beta - pharmacology ; Ubiquitin - metabolism ; Ubiquitin-Protein Ligases - deficiency ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Up-Regulation - physiology</subject><ispartof>Molecular cell, 2004-09, Vol.15 (5), p.825-831</ispartof><rights>2004 Cell Press</rights><rights>Copyright 2004 Cell Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-d79beda8db0de45600e372798b1d7d6755f79c89921c24be11a62b58b0940b263</citedby><cites>FETCH-LOGICAL-c435t-d79beda8db0de45600e372798b1d7d6755f79c89921c24be11a62b58b0940b263</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.molcel.2004.07.021$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15350225$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bai, Yongli</creatorcontrib><creatorcontrib>Yang, Chun</creatorcontrib><creatorcontrib>Hu, Kathrin</creatorcontrib><creatorcontrib>Elly, Chris</creatorcontrib><creatorcontrib>Liu, Yun-Cai</creatorcontrib><title>Itch E3 Ligase-Mediated Regulation of TGF-β Signaling by Modulating Smad2 Phosphorylation</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>Protein ubiquitination has been implicated in the intracellular biochemical events transduced by TGF-β receptor via different mechanisms including the degradation of Smads or their binding proteins. Here we show that loss of Itch E3 ligase in mouse embryonic fibroblasts (MEFs) results in reduced susceptibility of TGF-β-induced cell growth arrest and decreased phosphorylation of Smad2, without apparent alteration in protein levels for Smad2, Smad4, and Smad7 in Itch−/− MEFs. Itch promotes ubiquitination of Smad2 and augments Smad2 phosphorylation that requires an intact ligase activity of Itch. Moreover, Itch facilitates complex formation between TGF-β receptor and Smad2 and enhances TGF-β-induced transcription. This study reveals a previously unrecognized positive TGF-β signaling pathway via proteolysis-independent ubiquitination.</description><subject>Animals</subject><subject>Cell Division - drug effects</subject><subject>Cell Division - genetics</subject><subject>Cells, Cultured</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Female</subject><subject>Fetus</subject><subject>Fibroblasts - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Phosphorylation</subject><subject>Receptors, Transforming Growth Factor beta - metabolism</subject><subject>Signal Transduction - physiology</subject><subject>Smad2 Protein</subject><subject>Trans-Activators - metabolism</subject><subject>Transcription, Genetic - genetics</subject><subject>Transforming Growth Factor beta - biosynthesis</subject><subject>Transforming Growth Factor beta - genetics</subject><subject>Transforming Growth Factor beta - pharmacology</subject><subject>Ubiquitin - metabolism</subject><subject>Ubiquitin-Protein Ligases - deficiency</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><subject>Up-Regulation - physiology</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1u1DAQxy0EoqXwBgj5xC1h7PgjuSChqi2VtgLRcuFi-WN216skXuIs0r4WD8Iz4ZKVuMFpZqTff0bzI-Q1g5oBU-929ZB6j33NAUQNugbOnpBzBp2uBFPi6annWskz8iLnHQATsu2ekzMmGwmcy3Py7Xb2W3rV0FXc2IzVHYZoZwz0C24OvZ1jGmla04eb6-rXT3ofN6Pt47ih7kjvUvhDlOl-sIHTz9uU99s0HZfcS_JsbfuMr071gny9vnq4_FitPt3cXn5YVV40cq6C7hwG2wYHAYVUANhorrvWsaCD0lKudefbruPMc-GQMau4k62DToDjqrkgb5e9-yl9P2CezRBzEdPbEdMhG6Xa8qyW_wVZCxIaEAUUC-inlPOEa7Of4mCno2FgHuWbnVnkm0f5BrQp8kvszWn_wQ0Y_oZOtgvwfgGw6PgRcTLZRxx9cT6hn01I8d8XfgNqzpak</recordid><startdate>20040910</startdate><enddate>20040910</enddate><creator>Bai, Yongli</creator><creator>Yang, Chun</creator><creator>Hu, Kathrin</creator><creator>Elly, Chris</creator><creator>Liu, Yun-Cai</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20040910</creationdate><title>Itch E3 Ligase-Mediated Regulation of TGF-β Signaling by Modulating Smad2 Phosphorylation</title><author>Bai, Yongli ; Yang, Chun ; Hu, Kathrin ; Elly, Chris ; Liu, Yun-Cai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c435t-d79beda8db0de45600e372798b1d7d6755f79c89921c24be11a62b58b0940b263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Cell Division - drug effects</topic><topic>Cell Division - genetics</topic><topic>Cells, Cultured</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Female</topic><topic>Fetus</topic><topic>Fibroblasts - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Phosphorylation</topic><topic>Receptors, Transforming Growth Factor beta - metabolism</topic><topic>Signal Transduction - physiology</topic><topic>Smad2 Protein</topic><topic>Trans-Activators - metabolism</topic><topic>Transcription, Genetic - genetics</topic><topic>Transforming Growth Factor beta - biosynthesis</topic><topic>Transforming Growth Factor beta - genetics</topic><topic>Transforming Growth Factor beta - pharmacology</topic><topic>Ubiquitin - metabolism</topic><topic>Ubiquitin-Protein Ligases - deficiency</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bai, Yongli</creatorcontrib><creatorcontrib>Yang, Chun</creatorcontrib><creatorcontrib>Hu, Kathrin</creatorcontrib><creatorcontrib>Elly, Chris</creatorcontrib><creatorcontrib>Liu, Yun-Cai</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bai, Yongli</au><au>Yang, Chun</au><au>Hu, Kathrin</au><au>Elly, Chris</au><au>Liu, Yun-Cai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Itch E3 Ligase-Mediated Regulation of TGF-β Signaling by Modulating Smad2 Phosphorylation</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2004-09-10</date><risdate>2004</risdate><volume>15</volume><issue>5</issue><spage>825</spage><epage>831</epage><pages>825-831</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>Protein ubiquitination has been implicated in the intracellular biochemical events transduced by TGF-β receptor via different mechanisms including the degradation of Smads or their binding proteins. Here we show that loss of Itch E3 ligase in mouse embryonic fibroblasts (MEFs) results in reduced susceptibility of TGF-β-induced cell growth arrest and decreased phosphorylation of Smad2, without apparent alteration in protein levels for Smad2, Smad4, and Smad7 in Itch−/− MEFs. Itch promotes ubiquitination of Smad2 and augments Smad2 phosphorylation that requires an intact ligase activity of Itch. Moreover, Itch facilitates complex formation between TGF-β receptor and Smad2 and enhances TGF-β-induced transcription. This study reveals a previously unrecognized positive TGF-β signaling pathway via proteolysis-independent ubiquitination.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>15350225</pmid><doi>10.1016/j.molcel.2004.07.021</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Cell Division - drug effects Cell Division - genetics Cells, Cultured DNA-Binding Proteins - metabolism Female Fetus Fibroblasts - metabolism Male Mice Mice, Knockout Phosphorylation Receptors, Transforming Growth Factor beta - metabolism Signal Transduction - physiology Smad2 Protein Trans-Activators - metabolism Transcription, Genetic - genetics Transforming Growth Factor beta - biosynthesis Transforming Growth Factor beta - genetics Transforming Growth Factor beta - pharmacology Ubiquitin - metabolism Ubiquitin-Protein Ligases - deficiency Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Up-Regulation - physiology |
| title | Itch E3 Ligase-Mediated Regulation of TGF-β Signaling by Modulating Smad2 Phosphorylation |
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