REGULATION OF CASEIN KINASE-I-EPSILON AND CASEIN KINASE-I-DELTA BY ANIN-VIVO FUTILE PHOSPHORYLATION CYCLE

Casein kinase I delta (CKI delta) and casein kinase I epsilon (CKI eps ilon) have been implicated in the response to DNA damage, but the unde rstanding of how these kinases are regulated remains incomplete. In vi tro, these kinases rapidly autophosphorylate, predominantly on their c arboxyl-terminal extensions, and this autophosphorylation markedly inh ibits 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-perme able serine/threonine phosphatase inhibitors okadaic acid or calyculin A leads to rapid increases in kinase intramolecular autophosphorylati on. Since CKI autophosphorylation decreases kinase activity, this dyna mic autophosphorylation/dephosphorylation cycle provides a mechanism f or kinase regulation in vivo.