Casein kinase 1 delta activates human recombinant deoxycytidine kinase by Ser-74 phosphorylation, but is not involved in the in vivo regulation of its activity

[摘要]：Deoxycytidine kinase (dCK) is a key enzyme in the salvage of deoxynucleosides and in the activation of several anticancer and antiviral nucleoside analogues We recently showed that dCK was activated in vivo by phosphorylation of Ser-74 However, the protein kinase responsible was not identified Ser-74 is located downstream a Glu-rich region, presenting similarity with the consensus phosphorylation motif of casein kinase 1 (CKI), and particularly of CKI delta We showed that recombinant CKI delta phosphorylated several residues of bacterially overexpressed dCK Ser-74, but also Set-11, Ser-15, and Thr-72 Phosphorylation of dCK by CKI 6 correlated with Increased activity reaching at least 4-fold Site-directed mutagenesis demonstrated that only Ser-74 phosphorylation was involved in dCK activation by CKI delta, strengthening the key role of this residue in the control of dCK activity. However, neither CKI delta inhibitors nor CKI delta s1RNA-mediated knock-down modified Ser-74 phosphorylation or dCK activity in cultured cells Moreover, these approaches did not prevent dCK activation induced by treatments enhancing Ser-74 phosphorylation Taken together, the data preclude a role of CKI delta in the regulation of dCK activity in vivo Nevertheless, phosphorylation of dCK by CKI delta could be a useful tool for elucidating the influence of Ser-74 phosphorylation on the structure activity relationships in the enzyme (C) 2010 Elsevier Inc. All rights reserved

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