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dc.contributor.authorZarich-Dimitrievich, Natasha 
dc.contributor.authorAnta, Begoña
dc.contributor.authorFernández-Medarde, Alberto
dc.contributor.authorBallester, Alicia 
dc.contributor.authorde Lucas, Maria Pilar 
dc.contributor.authorCamara, Ana Belen 
dc.contributor.authorAnta-Felez, Berta 
dc.contributor.authorOliva-Martinez, Jose Luis 
dc.contributor.authorRojas-Cabañeros, Jose Maria 
dc.contributor.authorSantos, Eugenio
dc.date.accessioned2019-04-09T11:35:40Z
dc.date.available2019-04-09T11:35:40Z
dc.date.issued2019-01-04
dc.identifier.citationOncogenesis. 2019 Jan 4;8(1):2.es_ES
dc.identifier.issn2157-9024es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7441
dc.description.abstractSos1 is an universal, widely expressed Ras guanine nucleotide-exchange factor (RasGEF) in eukaryotic cells. Its N-terminal HD motif is known to be involved in allosteric regulation of Sos1 GEF activity through intramolecular interaction with the neighboring PH domain. Here, we searched for other cellular proteins also able to interact productively with the Sos1 HD domain. Using a yeast two-hybrid system, we identified the interaction between the Sos1 HD region and CSN3, the third component of the COP9 signalosome, a conserved, multi-subunit protein complex that functions in the ubiquitin-proteasome pathway to control degradation of many cellular proteins. The interaction of CSN3 with the HD of Sos1 was confirmed in vitro by GST pull-down assays using truncated mutants and reproduced in vivo by co-immunoprecipitation with the endogenous, full-length cellular Sos1 protein. In vitro kinase assays showed that PKD, a COP9 signalosome-associated-kinase, is able to phosphorylate Sos1. The intracellular levels of Sos1 protein were clearly diminished following CSN3 or PKD knockdown. A sizable fraction of the endogenous Sos1 protein was found ubiquitinated in different mammalian cell types. A significant reduction of RasGTP formation upon growth factor stimulation was also observed in CSN3-silenced as compared with control cells. Our data suggest that the interaction of Sos1 with the COP9 signalosome and PKD plays a significant role in maintenance of cellular Sos1 protein stability and homeostasis under physiological conditions and raises the possibility of considering the CSN/PKD complex as a potential target for design of novel therapeutic drugs.es_ES
dc.description.sponsorshipWe thank R Brent for the pJG45-HeLa library and R. Jorge for help with yeast two-hybrid screening. J.M.R. received grant support from MINECO-FEDER (SAF2016-78852-R), ISCIII-MINECO (FIS-Intrasalud PI13/00703) and Spanish Association against Cancer (AECC). E.S. and A.F.M. were supported by grants from ISCIII-MINECO (FIS PI16/02137), JCyL (SA043U16-UIC 076) and Solorzano Foundation. E.S. and J.M.R. were also supported by ISCIII-RETIC (groups RTICC-RD12/0036/0001 and RTICC-RD12/0036/0021, respectively) and by CIBERONC (groups CB16/12/00352 and CB16/12/00273, respectively). Research co-financed by FEDER funds.es_ES
dc.language.isoenges_ES
dc.publisherNature Publishing Groupes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleThe CSN3 subunit of the COP9 signalosome interacts with the HD region of Sos1 regulating stability of this GEF proteines_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID30631038es_ES
dc.format.volume8es_ES
dc.format.number1es_ES
dc.format.page2es_ES
dc.identifier.doi10.1038/s41389-018-0111-1es_ES
dc.contributor.funderJunta de Castilla y León
dc.contributor.funderFundación Solorzano
dc.contributor.funderInstituto de Salud Carlos III - ISCIII
dc.contributor.funderAsociación Española Contra el Cáncer
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)
dc.description.peerreviewedes_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41389-018-0111-1es_ES
dc.identifier.journalOncogenesises_ES
dc.repisalud.centroISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)es_ES
dc.repisalud.institucionISCIIIes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2016-78852-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI13/00703es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI16/02137es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0036/0001es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RD12/0036/0021es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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