Fig. 4. How the MEN is wired. The basic interactions among components of the MEN and some of its regulators are shown. Orange ball and stick symbols indicate inhibitory events. Green arrows indicate activating events. Purple arrows indicate substrates of Cdc14p. In all the cases indicated (except Lte1p, where this has not been assessed), the protein is activated to perform its function as a result of dephosphorylation by Cdc14p. The large purple arrows indicate that events are brought about by the indicated proteins, while the black arrow represents release of Cdc14p from the nucleolus. The grey ovals indicate functional groups of proteins. The gray box is meant to represent the Nud1p-based scaffold, upon which the MEN signaling proteins assemble at the spindle pole body. As in Fig. 3, red boxes indicate inhibitors of MEN components, and protein kinases are in yellow boxes. Panel A shows the state of the regulators of mitotic exit in early mitosis, before all the chromosomes have attached to the spindle. The spindle checkpoint blocks both the degradation of Cdc28p-CLB and activation of the FEAR proteins. The phosphoprotein phosphatase Cdc14p is sequestered in the nucleolus, and activated Cdc28p-CLB inhibits formation of APC/C^Cdh1p and activation of Cdc15p. Panel B shows the state of the regulators of mitotic exit during anaphase. The FEAR proteins release Cdc14p from the nucleolus. Cdc5p also inhibits Bfa1p, allowing Tem1p to accumulate in the GTP-bound form. One of the substrates of Cdc14p is Cdc15p, activating MEN signaling. This keeps Cdc14p out of the nucleolus and activates Dbf2p-Mob1p, which bring about cytokinesis and help maintain Cdc14p outside the nucleolus. Cdc14p increases the level of the CKI Sic1p, both by increasing its expression via Swi5p and by preventing degradation of Sic1p. It also targets Cdh1p, allowing formation of APC/C^Cdh1p to promote mitotic cyclin destruction during the M-G1 transition. Further details are given in the text. Panel C shows how this self perpetuating mitotic exit circuit is broken to allow B-type cyclins to accumulate in preparation for S-phase. Cdc14 promotes expression of Amn1p (see text for details), which directly interferes with the association of Cdc15p and Tem1p. Another target of Cdc14p is Bfa1p, which reactivates it, thereby promoting GTP hydrolysis by Tem1p and inactivation of signaling. Finally, the FEAR proteins Spo12p and Cdc5p are targets of APC/C^Cdh1p, which decreases FEAR activity. The reduction of MEN and FEAR activity is presumed to result in the return of Cdc14p to the nucleolus, although how this is achieved is not clear. Finally, Amn1p degradation is promoted through phosphorylation by activated Cdc28p-CLN, which allows Tem1p-Cdc15p interaction to occur later in the cycle.