Figure 6

The interplay between Cdk1 and mitotic exit. Phosphorylation of Pds1 by Cdk1 results in nuclear import of the inactive Pds1-Esp1 complex, while phosphorylation of Pds1 on other Cdk1 sites protects it from degradation until cells are ready to initiate anaphase. Activation of the FEAR pathway and anaphase onset are encouraged by dephosphorylation of Cdk1 sites on Pds1 by the phosphatase Cdc14, which leads to degradation of Pds1 by the APC. Liberated from its inhibitor, Esp1 can now cleave cohesins and inhibit the phosphatase PP2A^Cdc55. Downregulation of PP2A^Cdc55 shifts the balance from unphosphorylated Net1 to phosphorylated Net1, which is mediated by both Cdc5 as well as Cdk1, and results in dissociation of Cdc14 from Net1 and its release from the nucleolus. The release of a small amount of Cdc14 creates a positive feedback loop (green arrow) in which Cdc14 further dephosphorylates and thereby destabilizes Pds1, thus releasing more Cdc14. Downregulation of PP2A^Cdc55 also leads to a shift in the balance of unphosphorylated, active Bfa1-Bub2 to phosphorylated, inactive Bfa1-Bub2 (mediated by Cdc5), and downregulation of the GAP activity of Bub2 permits activation of the small GTPase Tem1. Lte1 may not directly activate Tem1, but rather indirectly through inhibiting Bfa1 by regulating its localization (dashed lines). Activation of Tem1 triggers the MEN, which provides the sustained Cdc14 activity that is necessary to exit from mitosis. Full activation of the MEN also requires dephosphorylation of the Cdk1 sites on Cdc15 and Mob1 by Cdc14.