Regulation of casein kinase i
Casein kinase I ( (CKIf) is a member of (he CKI gene family, members of which are involved in the control of SV40 DNA replication. DNA repair, and cell metabolism. The mechanisms that regulate CKIf activity and substrate specificity are not well understood. We report that, recomhinant CKIf, which contains a highly phosphorylated 123 ammo arid carboxy-terminal extension not present is CKIo, is substantially less active than CKIa in phosphorylating a number of substrates, including SV40 largo T antigen, and is unable to inhibit the initiation of SV40 DNA replication. Two mechanisms for the activation of CKIf have been identified. One, limited proteolysis of OKI products -A protease-resistant amino-terminal 39 kDa core kinase with enhanced activity. Two, phosphatase treatment of CKIf activated the kinase five- to twenty-fold towards T antigen. Similar treatment of CKIa and a truncated form of CKIf produced only a two-fold activation. Notably, this activation was transient; re-autophosphorylation lead to a rapid down-regulation of the kinase within five minutes. These results suggest that autoinhibition by the carboxy-terminal domain is a general mechanism for CKI family regulation. Phosphatase treatment also activated CKIe. towards the novel substrates I/tBa and Kts-1. Intra-molecular autophosphorylation of CKit also rapidly inactivates the kinase. However, in all cells and tissue examined CKIf is found in the dephosphorylated, active state. CKIf is actively maintained in this active state by a futile cycle of phosphorylation, as treatment of cells with phosphatase inhibitors leads to rapid kinase phosphorylation and inactivation. Physiologic stimuli that lead to CKIf inactivation are currently being investigated.
Virshup, D; Oietzen, K; Rivers, A; Utah, U
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