Figure 7.

Role of Cdc5 in exit from mitosis. Cdc5 may promote Cdc14 early anaphase release (FEAR) in part by phosphorylating Net1 directly (dotted arrow), and by activating an unknown Cdc14 dissociation factor (X). Subsequent activation of the MEN is important to sustain the transient Cdc14 release effected by the FEAR pathway. In the absence of MEN activity, Cdc14 returns to the nucleolus and cells arrest in late anaphase (bottom right). In the presence of MEN activity, Clb/CDK is shut off and cells exit mitosis (top right). The mechanism of action of MEN remains unknown, but activation of MEN correlates with appearance of Cdc14 in the cytoplasm [26], and mutation of known nuclear transport regulators renders mitotic exit independent of CDC15 function [35]. Together, these observations suggest that the MEN may promote exit by biasing the nucleocytoplasmic distribution of Cdc14. In addition to its role in the FEAR pathway, Cdc5 impinges positively on the MEN by several mechanisms, including: (i) Cdc5 promotes Tem1 activation by promoting chromosome segregation [22], which by enabling optimal spindle elongation and penetration into the bud, helps satisfy the spindle positioning checkpoint [12]; (ii) Cdc5 promotes activation of Tem1 GTP-binding protein by inhibiting its negative regulator, the Bfa1/Bub2 GTPase-activating protein [29], and (iii) Cdc5 promotes activation of Dbf2 by an unknown, BUB2-independent mechanism (dashed line) [18].