Regulation of Casein Kinase I ε and Casein Kinase I δ by an in Vivo Futile Phosphorylation Cycle*
- From the ‡Division of Molecular Biology and Genetics, Department of Oncological Sciences, Huntsman Cancer Institute, the§Division of Hematology/Oncology, Department of Pediatrics, and the ¶Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah 84132
Abstract
Casein kinase I δ (CKIδ) and casein kinase I ε (CKIε) have been implicated in the response to DNA damage, but the understanding of how these kinases are regulated remains incomplete. In vitro, these kinases rapidly autophosphorylate, predominantly on their carboxyl-terminal extensions, and this autophosphorylation markedly inhibits kinase activity (Cegielska, A., Gietzen, K. F., Rivers, A., and Virshup, D. M. (1998) J. Biol. Chem. 273, 1357–1364). However, we now report that while these kinases are able to autophosphorylatein vivo, they are actively maintained in the dephosphorylated, active state by cellular protein phosphatases. Treatment of cells with the cell-permeable serine/threonine phosphatase inhibitors okadaic acid or calyculin A leads to rapid increases in kinase intramolecular autophosphorylation. Since CKI autophosphorylation decreases kinase activity, this dynamic autophosphorylation/dephosphorylation cycle provides a mechanism for kinase regulation in vivo.
Footnotes
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↵* This work was supported by National Institutes of Health Grant R01 CA71074 to DMV.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‖ To whom correspondence should be addressed: Dept. of Oncological Sciences, University of Utah, 50 North Medical Dr., 5C334 Health Sciences Center, Salt Lake City, UT 84132.Tel.: 801-585-3408; Fax: 801-581-3607; E-mail: david.virshup{at}genetics.utah.edu.
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↵1 The abbreviations used are: CKI, casein kinase I; DMEM, Dulbecco’s modified Eagle’s medium; HA, hemagglutinin; PAGE, polyacrylamide gel electrophoresis; PMSF, phenylmethylsulfonyl fluoride; PP2Ac, protein phosphatase 2A catalytic subunit.
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- Received March 9, 1998.
- Revision received April 24, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
