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dc.contributor.authorVázquez Cedeira, Marta
dc.contributor.authorBarcia Sanjurjo, Iria
dc.contributor.authorSanz García, Marta
dc.contributor.authorBarcia Viéitez, Ramiro
dc.contributor.authorLazo, Pedro A.
dc.date.accessioned2020-05-28T16:21:09Z
dc.date.available2020-05-28T16:21:09Z
dc.date.issued2011
dc.identifier.citationVázquez-Cedeira M, Barcia-Sanjurjo I, Sanz-García M, Barcia R, Lazo PA (2011) Differential Inhibitor Sensitivity between Human Kinases VRK1 and VRK2. PLoS ONE 6(8): e23235. https://doi.org/10.1371/journal.pone.0023235
dc.identifier.urihttp://hdl.handle.net/10347/22632
dc.description.abstractHuman vaccinia-related kinases (VRK1 and VRK2) are atypical active Ser-Thr kinases implicated in control of cell cycle entry, apoptosis and autophagy, and affect signalling by mitogen activated protein kinases (MAPK). The specific structural differences in VRK catalytic sites make them suitable candidates for development of specific inhibitors. In this work we have determined the sensitivity of VRK1 and VRK2 to kinase inhibitors, currently used in biological assays or in preclinical studies, in order to discriminate between the two proteins as well as with respect to the vaccinia virus B1R kinase. Both VRK proteins and vaccinia B1R are poorly inhibited by inhibitors of different types targeting Src, MEK1, B-Raf, JNK, p38, CK1, ATM, CHK1/2 and DNA-PK, and most of them have no effect even at 100 mM. Despite their low sensitivity, some of these inhibitors in the low micromolar range are able to discriminate between VRK1, VRK2 and B1R. VRK1 is more sensitive to staurosporine, RO31-8220 and TDZD8. VRK2 is more sensitive to roscovitine, RO 31–8220, Cdk1 inhibitor, AZD7762, and IC261. Vaccinia virus B1R is more sensitive to staurosporine, KU55933, and RO 31–8220, but not to IC261. Thus, the three kinases present a different pattern of sensitivity to kinase inhibitors. This differential response to known inhibitors can provide a structural framework for VRK1 or VRK2 specific inhibitors with low or no cross-inhibition. The development of highly specific VRK1 inhibitors might be of potential clinical use in those cancers where these kinases identify a clinical subtype with a poorer prognosis, as is the case of VRK1 in breast cancer
dc.description.sponsorshipM.V.-C. and M.S.-G. have predoctoral fellowships from JAE/CSIC. I.B.-S. has a predoctoral fellowship from Zymofeed project of the Universidad de Santiago. This work was funded by grants from Ministerio de Educación, Ciencia e Innovación [SAF2010-14935 and CSD2007-0017], Junta de Castilla y León [CSI14A08 and GR15], Fundación Sandra Ibarra, and Kutxa-Fundación INBIOMED to P.A.L.; and from the Zymofeed project from Xunta de Galicia to R.B.
dc.language.isoeng
dc.publisherPLOS
dc.rights© 2011 Vázquez-Cedeira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/
dc.subjectVRK1
dc.subjectVRK2
dc.subjectHuman vaccinia
dc.subjectprotein kinases
dc.subjectMitogen
dc.titleDifferential inhibitor sensitivity between human kinases VRK1 and VRK2
dc.typeinfo:eu-repo/semantics/article
dc.identifier.DOI10.1371/journal.pone.0023235
dc.relation.publisherversionhttps://doi.org/10.1371/journal.pone.0023235
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.e-issn1932-6203
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.contributor.affiliationUniversidade de Santiago de Compostela. Departamento de Bioquímica e Bioloxía Molecular
dc.description.peerreviewedSI


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© 2011 Vázquez-Cedeira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Except where otherwise noted, this item's license is described as  © 2011 Vázquez-Cedeira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited





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