Model of Cdc25 activation. During interphase, Cdc25 is held inactive via by inhibitory phosphorylation at Ser287 and 14-3-3 binding. Likewise, PP2A/B56δ maintains Thr138 in the dephosphorylated state. At the G2/M transition, Cdc25 is activated in a stepwise fashion. First, Cdk2 phosphorylates Thr138 which triggers the release of 14-3-3. Phosphorylated keratin intermediate filaments assist in 14-3-3 removal from Cdc25 and Plx1 may also play a role in this process. Exposed Ser287 is then readily dephosphorylated by PP1, inducing the activation and nuclear translocation of Cdc25 and dephosphorylation of Cdc2. Once activated, Cdc2/Cyclin B phosphorylates multiple sites on Cdc25, enhancing its activity and preventing inactivation. Cdc2/Cyclin B may also activate the MAP kinase cascade which can phosphorylate Cdc25 in a parallel positive feedback loop.