Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation |
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| Authors: | Rachid Amsailale,Maxime Beyaert,Caroline Smal,Veerle Janssens,Eric Van Den Neste,Franç oise Bontemps |
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| Affiliation: | 1. de Duve Institute & Université Catholique de Louvain, B-1200 Brussels, Belgium;2. Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven, B-3000 Leuven, Belgium;3. Department of Hematology, Cliniques Universitaires Saint-Luc & Université Catholique de Louvain, B-1200 Brussels, Belgium |
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| Abstract: | Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation at concentrations reported to specifically target PP2A. In line with this, purified PP2A, but not PP1, dephosphorylated recombinant pSer-74-dCK. In cell lysates, the Ser-74-dCK phosphatase activity was found to be latent, Mn2+-activated, responsive to PP2A inhibitors, and diminished after PP2A-immunodepletion. Use of siRNAs allowed concluding definitively that PP2A constitutively dephosphorylates dCK in cells and negatively regulates its activity. |
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| Keywords: | dCK, deoxycytidine kinase pSer-74-dCK, dCK phosphorylated at Ser-74 ATM, ataxia telangiectasia mutated PP, Ser/Thr phosphatase PP1, Ser/Thr protein phosphatase 1 PP1c, catalytic subunit of PP1 PP2A, Ser/Thr protein phosphatase 2A PP2Ac, catalytic subunit of PP2A Fos, Fostriecin OA, okadaic acid siRNA, small interfering RNA HEK, human embryonic kidney |
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