RT Journal Article
T1 Differential inhibitor sensitivity between human kinases VRK1 and VRK2
A1 Vázquez Cedeira, Marta
A1 Barcia Sanjurjo, Iria
A1 Sanz García, Marta
A1 Barcia Viéitez, Ramiro
A1 Lazo, Pedro A.
K1 VRK1
K1 VRK2
K1 Human vaccinia
K1 protein kinases
K1 Mitogen
AB Human 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 structuraldifferences in VRK catalytic sites make them suitable candidates for development of specific inhibitors. In this work we havedetermined 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 proteinsand vaccinia B1R are poorly inhibited by inhibitors of different types targeting Src, MEK1, B-Raf, JNK, p38, CK1, ATM, CHK1/2and DNA-PK, and most of them have no effect even at 100 mM. Despite their low sensitivity, some of these inhibitors in thelow 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 virusB1R is more sensitive to staurosporine, KU55933, and RO 31–8220, but not to IC261. Thus, the three kinases present adifferent pattern of sensitivity to kinase inhibitors. This differential response to known inhibitors can provide a structuralframework for VRK1 or VRK2 specific inhibitors with low or no cross-inhibition. The development of highly specific VRK1inhibitors might be of potential clinical use in those cancers where these kinases identify a clinical subtype with a poorerprognosis, as is the case of VRK1 in breast cancer
PB PLOS
YR 2011
FD 2011
LK http://hdl.handle.net/10347/22632
UL http://hdl.handle.net/10347/22632
LA eng
NO Vázquez-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
NO M.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.
DS Minerva
RD 23 abr 2026