Cylindromatosis Tumor Suppressor Protein (CYLD) Deubiquitinase is Necessary for Proper Ubiquitination and Degradation of the Epidermal Growth Factor Receptor
Cylindromatosis tumor suppressor protein (CYLD) is a deubiquitinase, best known as an essential negative regulator of the NFkB pathway. Previous studies have suggested an involvement of CYLD in epidermal growth factor (EGF)-dependent signal transduction as well, as it was found enriched within the t...
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| Veröffentlicht in: | Molecular & cellular proteomics 2017-08, Vol.16 (8), p.1433-1446 |
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| creator | Sanchez-Quiles, Virginia Akimov, Vyacheslav Osinalde, Nerea Francavilla, Chiara Puglia, Michele Barrio-Hernandez, Inigo Kratchmarova, Irina Olsen, Jesper V. Blagoev, Blagoy |
| description | Cylindromatosis tumor suppressor protein (CYLD) is a deubiquitinase, best known as an essential negative regulator of the NFkB pathway. Previous studies have suggested an involvement of CYLD in epidermal growth factor (EGF)-dependent signal transduction as well, as it was found enriched within the tyrosine-phosphorylated complexes in cells stimulated with the growth factor. EGF receptor (EGFR) signaling participates in central cellular processes and its tight regulation, partly through ubiquitination cascades, is decisive for a balanced cellular homeostasis. Here, using a combination of mass spectrometry-based quantitative proteomic approaches with biochemical and immunofluorescence strategies, we demonstrate the involvement of CYLD in the regulation of the ubiquitination events triggered by EGF. Our data show that CYLD regulates the magnitude of ubiquitination of several major effectors of the EGFR pathway by assisting the recruitment of the ubiquitin ligase Cbl-b to the activated EGFR complex. Notably, CYLD facilitates the interaction of EGFR with Cbl-b through its Tyr15 phosphorylation in response to EGF, which leads to fine-tuning of the receptor's ubiquitination and subsequent degradation. This represents a previously uncharacterized strategy exerted by this deubiquitinase and tumors suppressor for the negative regulation of a tumorigenic signaling pathway. |
| doi_str_mv | 10.1074/mcp.M116.066423 |
| format | Article |
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Previous studies have suggested an involvement of CYLD in epidermal growth factor (EGF)-dependent signal transduction as well, as it was found enriched within the tyrosine-phosphorylated complexes in cells stimulated with the growth factor. EGF receptor (EGFR) signaling participates in central cellular processes and its tight regulation, partly through ubiquitination cascades, is decisive for a balanced cellular homeostasis. Here, using a combination of mass spectrometry-based quantitative proteomic approaches with biochemical and immunofluorescence strategies, we demonstrate the involvement of CYLD in the regulation of the ubiquitination events triggered by EGF. Our data show that CYLD regulates the magnitude of ubiquitination of several major effectors of the EGFR pathway by assisting the recruitment of the ubiquitin ligase Cbl-b to the activated EGFR complex. Notably, CYLD facilitates the interaction of EGFR with Cbl-b through its Tyr15 phosphorylation in response to EGF, which leads to fine-tuning of the receptor's ubiquitination and subsequent degradation. This represents a previously uncharacterized strategy exerted by this deubiquitinase and tumors suppressor for the negative regulation of a tumorigenic signaling pathway.</description><identifier>ISSN: 1535-9476</identifier><identifier>EISSN: 1535-9484</identifier><identifier>DOI: 10.1074/mcp.M116.066423</identifier><identifier>PMID: 28572092</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Cascades ; Cbl protein ; Cbl-b protein ; Chromatography, Liquid ; Degradation ; Deubiquitinating Enzyme CYLD - genetics ; Deubiquitinating Enzyme CYLD - metabolism ; Epidermal growth factor ; Epidermal growth factor receptors ; ErbB Receptors - metabolism ; HeLa Cells ; Homeostasis ; Humans ; Immunofluorescence ; Mass spectrometry ; Mass spectroscopy ; NF-κB protein ; Phosphorylation ; Proteolysis ; Proteomics ; Proto-Oncogene Proteins c-cbl - metabolism ; Recruitment ; Signal transduction ; Signaling ; Tandem Mass Spectrometry ; Tumor suppressor genes ; Tumor suppressor proteins ; Tumors ; Tyrosine ; Tyrosine - metabolism ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitination</subject><ispartof>Molecular & cellular proteomics, 2017-08, Vol.16 (8), p.1433-1446</ispartof><rights>2017 © 2017 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2017 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><rights>Copyright American Society for Biochemistry and Molecular Biology Aug 2017</rights><rights>2017 by The American Society for Biochemistry and Molecular Biology, Inc. 2017 The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c537t-df19f3f153cdc008de1efb3fb0f21750b4e1b49d5f9a7b79edb0876a5590061a3</citedby><cites>FETCH-LOGICAL-c537t-df19f3f153cdc008de1efb3fb0f21750b4e1b49d5f9a7b79edb0876a5590061a3</cites><orcidid>0000-0002-3596-0066</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546196/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546196/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28572092$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sanchez-Quiles, Virginia</creatorcontrib><creatorcontrib>Akimov, Vyacheslav</creatorcontrib><creatorcontrib>Osinalde, Nerea</creatorcontrib><creatorcontrib>Francavilla, Chiara</creatorcontrib><creatorcontrib>Puglia, Michele</creatorcontrib><creatorcontrib>Barrio-Hernandez, Inigo</creatorcontrib><creatorcontrib>Kratchmarova, Irina</creatorcontrib><creatorcontrib>Olsen, Jesper V.</creatorcontrib><creatorcontrib>Blagoev, Blagoy</creatorcontrib><title>Cylindromatosis Tumor Suppressor Protein (CYLD) Deubiquitinase is Necessary for Proper Ubiquitination and Degradation of the Epidermal Growth Factor Receptor</title><title>Molecular & cellular proteomics</title><addtitle>Mol Cell Proteomics</addtitle><description>Cylindromatosis tumor suppressor protein (CYLD) is a deubiquitinase, best known as an essential negative regulator of the NFkB pathway. Previous studies have suggested an involvement of CYLD in epidermal growth factor (EGF)-dependent signal transduction as well, as it was found enriched within the tyrosine-phosphorylated complexes in cells stimulated with the growth factor. EGF receptor (EGFR) signaling participates in central cellular processes and its tight regulation, partly through ubiquitination cascades, is decisive for a balanced cellular homeostasis. Here, using a combination of mass spectrometry-based quantitative proteomic approaches with biochemical and immunofluorescence strategies, we demonstrate the involvement of CYLD in the regulation of the ubiquitination events triggered by EGF. Our data show that CYLD regulates the magnitude of ubiquitination of several major effectors of the EGFR pathway by assisting the recruitment of the ubiquitin ligase Cbl-b to the activated EGFR complex. Notably, CYLD facilitates the interaction of EGFR with Cbl-b through its Tyr15 phosphorylation in response to EGF, which leads to fine-tuning of the receptor's ubiquitination and subsequent degradation. This represents a previously uncharacterized strategy exerted by this deubiquitinase and tumors suppressor for the negative regulation of a tumorigenic signaling pathway.</description><subject>Cascades</subject><subject>Cbl protein</subject><subject>Cbl-b protein</subject><subject>Chromatography, Liquid</subject><subject>Degradation</subject><subject>Deubiquitinating Enzyme CYLD - genetics</subject><subject>Deubiquitinating Enzyme CYLD - metabolism</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>ErbB Receptors - metabolism</subject><subject>HeLa Cells</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunofluorescence</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>NF-κB protein</subject><subject>Phosphorylation</subject><subject>Proteolysis</subject><subject>Proteomics</subject><subject>Proto-Oncogene Proteins c-cbl - metabolism</subject><subject>Recruitment</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Tandem Mass Spectrometry</subject><subject>Tumor suppressor genes</subject><subject>Tumor suppressor proteins</subject><subject>Tumors</subject><subject>Tyrosine</subject><subject>Tyrosine - metabolism</subject><subject>Ubiquitin</subject><subject>Ubiquitin-protein ligase</subject><subject>Ubiquitination</subject><issn>1535-9476</issn><issn>1535-9484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUtv1DAUhSMEoqVlzQ5ZYlMWM7UTO4k3SGj6AGmAqo8FK8uxrzuuEju1naL-GP4rHqWMAImVj-XvHt3jUxRvCF4S3NDjQY3LL4TUS1zXtKyeFfuEVWzBaUuf73RT7xWvYrzDuMSkYS-LvbJlTYl5uV_8XD321ungB5l8tBFdT4MP6GoaxwAxZnkRfALr0NHq-_rkPTqBqbP3k03WyQgoT3wFlUkZHpGZ8RECutlByXqHpNN58jZIPd-9QWkD6HS0GsIge3Qe_I-0QWdSpWxymS3HLA6LF0b2EV4_nQfFzdnp9erTYv3t_PPq43qhWNWkhTaEm8rkuEorjFsNBExXmQ6bMgfGHQXSUa6Z4bLpGg66w21TS8Y4xjWR1UHxYfYdp24ArcClIHsxBjvkXMJLK_5-cXYjbv2DYIzWhNfZ4OjJIPj7CWISg40K-l468FMUhGPWVKwmW_TdP-idn4LL8TLVUtxWuKWZOp4pFXyMAcxuGYLFtnqRqxfb6sVcfZ54-2eGHf-76wzwGYD8kw8WgojKglOgbQCVhPb2v-a_AE3Lwcs</recordid><startdate>20170801</startdate><enddate>20170801</enddate><creator>Sanchez-Quiles, Virginia</creator><creator>Akimov, Vyacheslav</creator><creator>Osinalde, Nerea</creator><creator>Francavilla, Chiara</creator><creator>Puglia, Michele</creator><creator>Barrio-Hernandez, Inigo</creator><creator>Kratchmarova, Irina</creator><creator>Olsen, Jesper V.</creator><creator>Blagoev, Blagoy</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><general>The American Society for Biochemistry and Molecular Biology</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>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3596-0066</orcidid></search><sort><creationdate>20170801</creationdate><title>Cylindromatosis Tumor Suppressor Protein (CYLD) Deubiquitinase is Necessary for Proper Ubiquitination and Degradation of the Epidermal Growth Factor Receptor</title><author>Sanchez-Quiles, Virginia ; Akimov, Vyacheslav ; Osinalde, Nerea ; Francavilla, Chiara ; Puglia, Michele ; Barrio-Hernandez, Inigo ; Kratchmarova, Irina ; Olsen, Jesper V. ; Blagoev, Blagoy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c537t-df19f3f153cdc008de1efb3fb0f21750b4e1b49d5f9a7b79edb0876a5590061a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Cascades</topic><topic>Cbl protein</topic><topic>Cbl-b protein</topic><topic>Chromatography, Liquid</topic><topic>Degradation</topic><topic>Deubiquitinating Enzyme CYLD - genetics</topic><topic>Deubiquitinating Enzyme CYLD - metabolism</topic><topic>Epidermal growth factor</topic><topic>Epidermal growth factor receptors</topic><topic>ErbB Receptors - metabolism</topic><topic>HeLa Cells</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Immunofluorescence</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>NF-κB protein</topic><topic>Phosphorylation</topic><topic>Proteolysis</topic><topic>Proteomics</topic><topic>Proto-Oncogene Proteins c-cbl - metabolism</topic><topic>Recruitment</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Tandem Mass Spectrometry</topic><topic>Tumor suppressor genes</topic><topic>Tumor suppressor proteins</topic><topic>Tumors</topic><topic>Tyrosine</topic><topic>Tyrosine - metabolism</topic><topic>Ubiquitin</topic><topic>Ubiquitin-protein ligase</topic><topic>Ubiquitination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sanchez-Quiles, Virginia</creatorcontrib><creatorcontrib>Akimov, Vyacheslav</creatorcontrib><creatorcontrib>Osinalde, Nerea</creatorcontrib><creatorcontrib>Francavilla, Chiara</creatorcontrib><creatorcontrib>Puglia, Michele</creatorcontrib><creatorcontrib>Barrio-Hernandez, Inigo</creatorcontrib><creatorcontrib>Kratchmarova, Irina</creatorcontrib><creatorcontrib>Olsen, Jesper V.</creatorcontrib><creatorcontrib>Blagoev, Blagoy</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>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular & cellular proteomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sanchez-Quiles, Virginia</au><au>Akimov, Vyacheslav</au><au>Osinalde, Nerea</au><au>Francavilla, Chiara</au><au>Puglia, Michele</au><au>Barrio-Hernandez, Inigo</au><au>Kratchmarova, Irina</au><au>Olsen, Jesper V.</au><au>Blagoev, Blagoy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cylindromatosis Tumor Suppressor Protein (CYLD) Deubiquitinase is Necessary for Proper Ubiquitination and Degradation of the Epidermal Growth Factor Receptor</atitle><jtitle>Molecular & cellular proteomics</jtitle><addtitle>Mol Cell Proteomics</addtitle><date>2017-08-01</date><risdate>2017</risdate><volume>16</volume><issue>8</issue><spage>1433</spage><epage>1446</epage><pages>1433-1446</pages><issn>1535-9476</issn><eissn>1535-9484</eissn><abstract>Cylindromatosis tumor suppressor protein (CYLD) is a deubiquitinase, best known as an essential negative regulator of the NFkB pathway. Previous studies have suggested an involvement of CYLD in epidermal growth factor (EGF)-dependent signal transduction as well, as it was found enriched within the tyrosine-phosphorylated complexes in cells stimulated with the growth factor. EGF receptor (EGFR) signaling participates in central cellular processes and its tight regulation, partly through ubiquitination cascades, is decisive for a balanced cellular homeostasis. Here, using a combination of mass spectrometry-based quantitative proteomic approaches with biochemical and immunofluorescence strategies, we demonstrate the involvement of CYLD in the regulation of the ubiquitination events triggered by EGF. Our data show that CYLD regulates the magnitude of ubiquitination of several major effectors of the EGFR pathway by assisting the recruitment of the ubiquitin ligase Cbl-b to the activated EGFR complex. Notably, CYLD facilitates the interaction of EGFR with Cbl-b through its Tyr15 phosphorylation in response to EGF, which leads to fine-tuning of the receptor's ubiquitination and subsequent degradation. This represents a previously uncharacterized strategy exerted by this deubiquitinase and tumors suppressor for the negative regulation of a tumorigenic signaling pathway.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28572092</pmid><doi>10.1074/mcp.M116.066423</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-3596-0066</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Cascades Cbl protein Cbl-b protein Chromatography, Liquid Degradation Deubiquitinating Enzyme CYLD - genetics Deubiquitinating Enzyme CYLD - metabolism Epidermal growth factor Epidermal growth factor receptors ErbB Receptors - metabolism HeLa Cells Homeostasis Humans Immunofluorescence Mass spectrometry Mass spectroscopy NF-κB protein Phosphorylation Proteolysis Proteomics Proto-Oncogene Proteins c-cbl - metabolism Recruitment Signal transduction Signaling Tandem Mass Spectrometry Tumor suppressor genes Tumor suppressor proteins Tumors Tyrosine Tyrosine - metabolism Ubiquitin Ubiquitin-protein ligase Ubiquitination |
| title | Cylindromatosis Tumor Suppressor Protein (CYLD) Deubiquitinase is Necessary for Proper Ubiquitination and Degradation of the Epidermal Growth Factor Receptor |
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