Regulation of casein kinase I epsilon and casein kinase I delta by an in vivo futile phosphorylation cycle.
Casein kinase I delta (CKIdelta) and casein kinase I epsilon (CKIepsilon) 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 autophosphorylate in 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.
Rivers
A
A
Division of Molecular Biology and Genetics, Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84132, USA.
Gietzen
K F
KF
Vielhaber
E
E
Virshup
D M
DM
D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D047388:Casein Kinases; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008387:Marine Toxins; D051379:Mice; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008387:Marine Toxins; D010080:Oxazoles; D019319:Okadaic Acid; C059041:calyculin A; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D047388:Casein Kinases; D010749:Phosphoprotein Phosphatases