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Chk1 KA1 domain auto-phosphorylation stimulates biological activity and is linked to rapid proteasomal degradation

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dc.contributor.authorGong, Eun-Yeung-
dc.contributor.authorHernandez, Beatriz-
dc.contributor.authorHernandez Nielsen, Jessica-
dc.contributor.authorSmits, Veronique A. J.-
dc.contributor.authorFreire, Raimundo-
dc.contributor.authorGillespie, David A.-
dc.date.available2021-02-22T07:46:20Z-
dc.date.created2020-08-18-
dc.date.issued2018-12-
dc.identifier.issn2045-2322-
dc.identifier.urihttps://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/4148-
dc.description.abstractThe DNA damage-activated protein kinase Chk1 is known to undergo auto-phosphorylation, however the sites and functional significance of this modification remain poorly understood. We have identified two novel Chk1 auto-phosphorylation sites, threonines 378 and 382 (T378/382), located in a highly conserved motif within the C-terminal Kinase Associated 1 (KA1) domain. T378/382 occur within optimal consensus Chk1 phosphorylation motifs and substitution with phospho-mimetic aspartic acid residues results in a constitutively active mutant Chk1 kinase (Chk1-DD) that arrests cell cycle progression in G2 phase of the cell cycle in the absence of DNA damage. Remarkably, the mutant Chk1-DD protein is also subject to very rapid proteasomal degradation, with a half-life approximately one tenth that of wild-type Chk1. Consistent with this, T378/T382 auto-phosphorylation also accelerates the proteasomal degradation of constitutively active Chk1 KA1 domain structural mutants. T378/382 autophosphorylation and accelerated degradation of wild-type Chk1 occurs at low levels during unperturbed growth, but surprisingly, is not augmented in response to genotoxic stress. Taken together, these observations demonstrate that Chk1 T378/T382 auto-phosphorylation within the KA1 domain is linked to kinase activation and rapid proteasomal degradation, and suggest a non-canonical mechanism of regulation.-
dc.language영어-
dc.language.isoen-
dc.publisherNATURE PUBLISHING GROUP-
dc.titleChk1 KA1 domain auto-phosphorylation stimulates biological activity and is linked to rapid proteasomal degradation-
dc.typeArticle-
dc.contributor.affiliatedAuthorGong, Eun-Yeung-
dc.identifier.doi10.1038/s41598-018-35616-9-
dc.identifier.scopusid2-s2.0-85057596940-
dc.identifier.wosid000451879300012-
dc.identifier.bibliographicCitationSCIENTIFIC REPORTS, v.8-
dc.relation.isPartOfSCIENTIFIC REPORTS-
dc.citation.titleSCIENTIFIC REPORTS-
dc.citation.volume8-
dc.type.rimsART-
dc.type.docTypeArticle-
dc.description.journalClass1-
dc.description.isOpenAccessY-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
dc.relation.journalResearchAreaScience & Technology - Other Topics-
dc.relation.journalWebOfScienceCategoryMultidisciplinary Sciences-
dc.subject.keywordPlusKINASE-
dc.subject.keywordPlusAUTOINHIBITION-
dc.subject.keywordPlusDETERMINANTS-
dc.subject.keywordPlusACTIVATION-
dc.subject.keywordPlusCELLS-
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