Cdc14 is a phosphatase required for exit of mitosis (Bardin & Amon, 2001, Visintin et al., 1998). It functions essentially in late mitosis: cells carrying a defective mutation arrest in telophase with high CDK activity (Fitzpatrick et al., 1998; whereas overexpression of Cdc14 results in G1 arrest (Visintin et al., 1998). Cdc14 is the last element of MEN (Guacci et al., 1997; Bardin et al., 2000; Jaspersen et al., 1998; Jaspersen & Morgan, 2000).
Cdc14 triggers mitotic CDK inactivation, enabling cells to exit mitosis through
dephosphorylation and activation of the enemies of CDKs. Cdc14 is a dual-specificity
phosphatase, it removes the phosphate group on phospho-tyrosine and phospho-serine/threonine
(Taylor et al., 1997).
Cdc14 activates the
- Swi5, the transcription factor for Sic1 and Cdc6 (Visintin et al., 1998). By dephosphorylation of Swi5, Cdc14 promotes the translocation of Swi5 into the nucleus, thereby upregulating transcription of Sic1 and Cdc6.
- Sic1, stoichiometric inhibitor of the CDKs
(Visintin et al., 1998).
Sic1 is degraded throughout the cell cycle in a phosphorylation-dependent
manner. Dephosphorylation by Cdc14 promotes Sic1 stabilization. Cdc14 also
stabilizes Cdc6, since its degradation is SCF-regulated
(Perkins et al., 2001).
- Cdh1, an ancillary protein of the APC, responsible for the destruction of Clb2 (Visintin et al., 1998; Jaspersen et al., 1999; Zachariae et al., 1998). Dephosphorylation of Cdh1 promotes its association with APC, causing APC to be activated.
- Unknown target proteins. Since the triple mutant sic1∆ cdc6∆2-49 cdh1∆ exits from mitosis with high levels of CDKs (Cross, 2003), whereas cdc14ts arrests in telophase, Cdc14 must have another target besides Swi5, Sic1, Cdc6 and Cdh1.
- Cdc14 also dephosphorylates and activates Cdc15, thus facilitating Cdc14 release from the nucleolus. However, in cdc14ts mutant, the inactive Cdc14 protein is released, indicating that Cdc14 is not essential for the activation of Cdc15 (Jaspersen & Morgan, 2000).
Cdc14 level is constant throughout the cell cycle (Spellman et al., 1998).
Throughout G1, S/G2 and early mitosis, Cdc14 is inactive when it is sequestered in the nucleolus by association with Net1 and Sir2, forming an inactive complex called RENT (REgulator of Nucleolar silencing and Telophase) (Visintin et al., 1999; Shou et al., 1999). When Net1 is inactivated (via phosphorylation by Cdc5) (Shou et al., 2002a; Yoshida & Toh-e, 2002a), and MEN pathway is activated (Pereira et al., 2002), Cdc14 is released from the nucleolus to reach its targets in the nucleus (Sic1, Cdc6 and Cdh1) and the cytoplasm (Swi5). Then the cell is able to exit mitosis. Cdc14 is re-sequestered in late telophase (Pereira et al., 2002; Stegmeier et al., 2002).
Transient release of Cdc14: Two populations of Cdc14 are observed. A first pool of Cdc14 is released from the nucleolus by the FEAR (Cdc Fourteen Early Anaphase Release) pathway whose components are Cdc5, Slk9, Spo12 and Esp1 (Pereira et al., 2002; Saunders, 2002). However, this release, independent of MEN, is not enough to enable the cell to exit from mitosis. MEN (Mitotic Exit Network) activation is needed to maintain Cdc14 in its released state (Pereira et al., 2002). Recently, Visintin et al., 2003 proposed that Cdc14 release from the nucleolus occurs only when Cdc14 and Net1 are both phosphorylated. Cdc5 promotes Cdc14 release in two ways, it phosphorylates Cdc14 directly (thus causing a transient release), and by activating the MEN pathway, Cdc5 induces Net1 phosphorylation indirectly. These phosphorylation are necessary to maintain Cdc14 in the released state during late anaphase and telophase.
In our model, the hypothetical PPX acts functionally opposite to the FEAR pathway: in reality, Pds1 inhibits Cdc14 release by inhibiting an activator (Esp1 in the FEAR pathway); whereas in the model, Pds1 achieves the same goal by activating an inhibitor (PPX, which keeps Net1 dephosphorylated and active).