Regulation of transcriptional programs by Cdk1 during the cell cycle. Cdk1 is involved in positive and negative feedback loops that regulate transcriptional programs to control cell cycle progression. See text for details.

Cdk1 restricts the pheromone response pathway to the G1 phase of the cell cycle. (A), when pheromone is detected by the receptor during G1 phase (when Cdk1 activity is low), a signaling cascade that is mostly mediated by the βγ subunit of the heterotrimeric G protein prevents entry into S phase, polarizes the actin cytoskeleton towards the face of the cell with the highest pheromone concentration, and activates transcriptional programs. (B), binding of pheromone to the receptor outside of the G1 phase - when Cdk1 is active - does not trigger the pheromone signaling pathway because it is disconnected from its downstream components by Cdk1-mediated phosphorylation of Ste5, Ste20 and Far1. See text for details.

Cdk1 controls proteins involved chromosome segregation. Cdk1 controls chromosome cohesion by phosphorylating Pds1 and possibly the cohesin Scc1. Assembly of the mitotic spindle is also controlled by Cdk1, because it phosphorylates Spc42 and Mps1, which is important for SPB duplication, as well as Spc110, which may play a role in attachment of the SPB to the mitotic spindle. Cdk1 also prevents SPB re-duplication, but the molecular mechanism remains to be determined. Spindle positioning is mediated by Cdk1-dependent phosphorylation of Kar9, the SPB component Cnm67, and possibly Stu2. Later in the cell cycle Cdk1 phosphorylates Ase1, Bir1, Fin1 and Sli15 to modulate spindle stability and elongation.

Cdk1 modulates the activity of several DNA damage checkpoint proteins. DNA damage and replication stress are sensed by a number of proteins that activate the PIKKs Mec1 and Tel1. These kinases activate a signal transduction pathway consisting of the adaptor proteins Mrc1 and Rad9 and the kinases Rad53, Dun1 and Chk1. Cdk1 may phosphorylate Rad9 to boost the signaling cascade. Cdk1 also phosphorylates Rad53, which may prevent checkpoint adaptation, but which may also affect processes involved in cell morphogenesis. Together, Mec1, Tel1, Rad53, Dun1 and Chk1 phosphorylate a number of effector proteins (only a subset of effectors is shown in this figure) that mediate the DNA damage response. Several of these effectors are also targeted by Cdk1, although the consequence of simultaneous phosphorylation by Rad53 and Cdk1 is unclear. Mec1/Tel1 and Cdk1 directly phosphorylate Sae2 to stimulate its nuclease activity, which is important for resection of DSBs, thereby channeling DSBs into the HR pathway. Full resection of DSBs also requires the activity of Dna2 and Sgs1. Phosphorylation of Dna2 by Cdk1 increases its nuclear import, while Cdk1 may affect Sgs1 by phosphorylating Srs2, which leads to formation of subcomplexes consisting of Srs2, Srs2-Mre11 and Sgs1-Mre11. Mec1/Tel1 and Cdk1 also directly phosphorylate Cdc13, resulting in recruitment of telomerase and telomere elongation. See text for details.

Cdk1 and control of bud morphogenesis. Landmark proteins select the bud site, which is followed by recruitment and activation of Bud1, which in turn recruits and activates the small GTPase Cdc42. Cdk1 reinforces activation of Cdc42 by inhibiting the activity of the GAPs Bem2/3 and Rga2, and by phosphorylating the adaptor proteins Bem1 and Boi1/2. Cdk1 may also activate Cdc42 by phosphorylating the GEF Cdc24. GTP-bound Cdc42 then recruits Cla4, which mediates polarization of the actin cytoskeleton, which is required for bud growth. In addition, Cdk1 promotes the activity of the small GTPase Rho1 by inhibiting Bem2 and by activating the GEF Tus1, which supports bud growth. The septins Shs1 and Cdc3 are also phosphorylated by Cdk1, which may affect the mobility of Cdc3, while phosphorylation of Shs1 may affect the activity of Cdk1 by negative feedback in a later stage of the cell cycle. See text for details.

Cdk1 and regulation of DNA replication. During G1 phase of the cell cycle, when Cdk1 is inactive, cells assemble pre-RC complexes onto their origins of replication. When Cdk1 becomes active at the end of G1 phase it phosphorylates several components of the complex, and especially phosphorylation of Sld2 and Sld3 results in origin firing and initiation of DNA replication. After origin firing, several components dissociate and cannot re-assemble into replication-competent origins until they become dephosphorylated and Cdk1 becomes inactivated during G1, thus providing a mechanism for prevention of re-replication.

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.