differential inhibitor sensitivity between human kinases vrk1 and vrk2人类的激酶vrk1和vrk2之间微分抑制剂的敏感性.pdfVIP

Differential Inhibitor Sensitivity between Human Kinases VRK1 and VRK2 ´ 1 2 ´ 1 2 1 Marta Vazquez-Cedeira , Iria Barcia-Sanjurjo , Marta Sanz-Garcıa , Ramiro Barcia , Pedro A. Lazo * ´ ´ 1 Experimental Therapeutics and Translational Oncology Program, Instituto de Biologıa Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, Salamanca, Spain, ´ ´ 2 Departamento de Bioquımica y Biologıa Molecular, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain Abstract 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 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, RO- 31-