c-Abl phosphorylates E6AP and regulates its E3 ubiquitin ligase activity

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CHAN, Ai-Leen, Tamar GROSSMAN, Valentia ZUCKERMAN, Dafne CAMPIGLI DI GIAMMARTINO, Ofra MOSHEL, Martin SCHEFFNER, Brendon MONAHAN, Pat PILLING, Yong-Hui JIANG, Sue HAUPT, Ora SCHUELER-FURMAN, Ygal HAUPT, 2013. c-Abl phosphorylates E6AP and regulates its E3 ubiquitin ligase activity. In: Biochemistry. 52(18), pp. 3119-3129. ISSN 0006-2960. eISSN 1520-4995

@article{Chan2013-05-07c-Abl-25131, title={c-Abl phosphorylates E6AP and regulates its E3 ubiquitin ligase activity}, year={2013}, doi={10.1021/bi301710c}, number={18}, volume={52}, issn={0006-2960}, journal={Biochemistry}, pages={3119--3129}, author={Chan, Ai-Leen and Grossman, Tamar and Zuckerman, Valentia and Campigli Di Giammartino, Dafne and Moshel, Ofra and Scheffner, Martin and Monahan, Brendon and Pilling, Pat and Jiang, Yong-Hui and Haupt, Sue and Schueler-Furman, Ora and Haupt, Ygal} }

<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/25131"> <dc:contributor>Pilling, Pat</dc:contributor> <dc:contributor>Monahan, Brendon</dc:contributor> <dc:contributor>Jiang, Yong-Hui</dc:contributor> <dc:creator>Zuckerman, Valentia</dc:creator> <dc:creator>Monahan, Brendon</dc:creator> <dcterms:abstract xml:lang="eng">In human papillomavirus (HPV)-infected cells, the p53 tumor suppressor is tightly regulated by the HPV-E6-E6AP complex, which promotes it for proteasomal degradation. We previously demonstrated that c-Abl tyrosine kinase protects p53 from HPV-E6-E6AP complex-mediated ubiquitination and degradation under stress conditions. However, the underlying mechanism was not defined. In this study, we explored the possibility that c-Abl targets E6AP and thereby protects p53. We demonstrated that c-Abl interacts with and phosphorylates E6AP. We determined that the E3 ligase activity of E6AP is impaired in response to phosphorylation by c-Abl. We mapped the phosphorylation site to tyrosine 636 within the HECT catalytic domain of E6AP, and using substitution mutants, we showed that this residue dictates the E3 ligase activity of E6AP, in a substrate-specific manner. On the basis of the crystal structure of the HECT domain of E6AP, we propose a model in which tyrosine 636 plays a regulatory role in the oligomerization of E6AP, which is a process implicated in its E3 ubiquitin ligase activity. Our results suggest that c-Abl protects p53 from HPV-E6-E6AP complex-mediated degradation by phosphorylating E6AP and impairing its E3 ligase activity, thus providing a molecular explanation for the stress-induced protection of p53 in HPV-infected cells.</dcterms:abstract> <dc:rights>deposit-license</dc:rights> <dc:creator>Scheffner, Martin</dc:creator> <dc:creator>Campigli Di Giammartino, Dafne</dc:creator> <dc:creator>Moshel, Ofra</dc:creator> <dc:contributor>Haupt, Sue</dc:contributor> <dc:contributor>Scheffner, Martin</dc:contributor> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2013-11-26T18:43:13Z</dc:date> <dc:contributor>Zuckerman, Valentia</dc:contributor> <dc:creator>Chan, Ai-Leen</dc:creator> <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/25131"/> <dc:contributor>Haupt, Ygal</dc:contributor> <dc:language>eng</dc:language> <dc:contributor>Moshel, Ofra</dc:contributor> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2013-11-26T18:43:13Z</dcterms:available> <dc:creator>Schueler-Furman, Ora</dc:creator> <dc:contributor>Campigli Di Giammartino, Dafne</dc:contributor> <dcterms:title>c-Abl phosphorylates E6AP and regulates its E3 ubiquitin ligase activity</dcterms:title> <dc:contributor>Schueler-Furman, Ora</dc:contributor> <dc:creator>Haupt, Sue</dc:creator> <dc:contributor>Chan, Ai-Leen</dc:contributor> <dc:contributor>Grossman, Tamar</dc:contributor> <dcterms:bibliographicCitation>Biochemistry ; 52 (2013), 18. - S. 3119–3129</dcterms:bibliographicCitation> <dcterms:rights rdf:resource="http://nbn-resolving.org/urn:nbn:de:bsz:352-20140905103605204-4002607-1"/> <dc:creator>Jiang, Yong-Hui</dc:creator> <dc:creator>Haupt, Ygal</dc:creator> <dcterms:issued>2013-05-07</dcterms:issued> <dc:creator>Pilling, Pat</dc:creator> <dc:creator>Grossman, Tamar</dc:creator> </rdf:Description> </rdf:RDF>

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