Role for cyclin-dependent kinase 2 in mitosis exit

Mitosis requires cyclin-dependent kinase (cdk) 1-cyclin B activity [1]. Exi t from mitosis depends on the inactivation of the complex by the degradatio n of cyclin B [2]. Cdk2 is also active during mitosis [3, 4]. In Xenopus eg g extracts, cdk2 is primarily in complex with cyclin E, which is stable [5] . At the end of mitosis, downregulation of cdk2-cyclin E activity is accomp anied by inhibitory phosphorylation of cdk2 [6]. Here, we show that cdk2-cy clin E activity maintains cdk1-cyclin B during mitosis. At mitosis exit, cd k2 is inactivated prior to cdk1. The loss of cdk2 activity follows and depe nds upon an increase in protein kinase A (PKA) activity. Prematurely inacti vating cdk2 advances the time of cyclin B degradation and cdk1 inactivation . Blocking PKA, instead, stabilizes cdk2 activity and inhibits cyclin B deg radation and cdk1 inactivation. The stabilization of cdk1-cyclin B is also induced by a mutant cdk2-cyclin E complex that is resistant to inhibitory p hosphorylation. P21-Cip1, which inhibits both wild-type and mutant cdk2-cyc lin E, reverses mitotic arrest under either condition. Our findings indicat e that the proteolysis-independent downregulation of cdk2 activity at the e nd of mitosis depends on PKA and is required to activate the proteolysis ca scade that leads to mitosis exit.