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#Cdc14

3 public questions tagged with this topic.

Cell Cycle Regulation

Which phosphatase deactivates mitotic CDKs to promote exit from mitosis?

Lowering mitotic kinase activity requires collaboration between ubiquitin mediated cyclin destruction and phosphatase mediated substrate dephosphorylation. APC/C-Cdc20 degrades cyclin B reducing CDK1 catalytic availability, but hundreds of phosphorylated residues remain. Phosphatases execute erasure. In yeast, Cdc14 is dominant enzyme preferentially dephosphorylating proline-directed CDK sites, including Cdh1 to activate APC/C-Cdh1 for further cyclin clearance, Swi5 for Sic1 transcription and structural cytokinesis proteins. In metazoa, PP2A-B55 family is major mitotic exit phosphatase regulated by Greatwall kinase and its substrates ENSA and Arpp19; when Greatwall inhibited at anaphase onset through cyclin B degradation and PP1 activation, ENSA dephosphorylation releases PP2A-B55 active site allowing dephosphorylation of PRC1, ECT2, Nup53 and other mitotic targets essential for central spindle assembly and nuclear reformation. Dataset annotation assigning CDK1 as phosphatase is inaccurate; CDK1 is kinase itself deactivated during exit. CDC14A/B assist PP2A-B55. Inhibition of these phosphatases preserves hyperphosphorylated state leading to segregated but condensed chromosomes, failure of nuclear envelope reassembly and block of abscission. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Wurzenberger & Gerlich, Mitotic Phosphatases PP2A and Cdc14 in Exit, J Cell Biol 2011; NCBI Bookshelf, Regulation of Mitotic Exit.

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Cell Cycle Regulation

Which factor regulates the exit from mitosis?

Finishing mitosis demands comprehensive reversal of CDK1 mediated phosphorylations and elimination of cyclin B activity. Cdc14 family phosphatases coordinate this program. In budding yeast, Cdc14 resides sequestered in nucleolus bound to inhibitor Net1 also called Cfi1. Mitotic entry maintains sequestration via high CDK activity. In early anaphase, FEAR pathway comprising separase, Slk19 homodimer, Spo12, Zds1 and Zds2 induces transient release. Subsequently Mitotic Exit Network MEN, Hippo-like cascade of Tem1 GTPase localized at daughter spindle pole body, polo kinase Cdc15 and Dbf2-Mob1 complex, fully liberates Cdc14 through phosphorylation of Net1. Free phosphatase preferentially dephosphorylates CDK sites containing serine-proline followed by lysine, including APC/C coactivator Cdh1 shifting APC/C activity from Cdc20 to Cdh1, transcription factor Swi5 enabling Sic1 CDK inhibitor synthesis, and S-phase regulator Cdc15 reinforcing feedback. Sic1 accumulation plus cyclin B degradation extinguishes CDK1 activity, allowing spindle disassembly, actomyosin ring contraction via Hof1 and Inn1 dephosphorylation, and septum formation. In mammals, orthologous CDC14A/B collaborate with PP2A-B55 for mitotic exit. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Stegmeier & Amon, Closing Mitosis: Regulation of Cdc14 Phosphatase, Annu Rev Genet 2004; Bardin & Amon, MEN and Mitotic Exit.

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Cell Cycle Regulation

Which protein deactivates mitotic CDKs during mitotic exit?

Mitotic exit requires not only destruction of cyclin B but comprehensive reversal of CDK1-Cyclin B phosphorylation on hundreds of substrates. Specialized phosphatases execute this program. In budding yeast, Cdc14 is the master phosphatase. Most of the cell cycle it is sequestered in nucleolus bound to inhibitor Net1 or Cfi1. Two release pathways operate sequentially: the Cdc Fourteen Early Anaphase Release pathway involving separase, Slk19, Spo12 and Zds1/Zds2 provides transient liberation in early anaphase, while the Mitotic Exit Network composed of Tem1, Cdc15 and Dbf2-Mob1 kinases sustains release. Active Cdc14 preferentially dephosphorylates serine followed by proline with basic Lys in +3 position, matching CDK consensus, including targets Cdh1 converting APC/C coactivator from Cdc20 to Cdh1, Swi5 transcription factor enabling Sic1 inhibitor synthesis and Cdc15 reinforcing feedback. In mammals, CDC14A/B and PP2A-B55, regulated by Greatwall-ENSA pathway, fulfill analogous roles. Inhibition traps cells in late anaphase with segregated but condensed chromosomes unable to reform nuclei or undergo cytokinesis. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Stegmeier & Amon, Closing Mitosis: Role of Cdc14 Phosphatases, Annu Rev Genet 2004; Alberts et al., Chapter 17, Mitotic Exit Control.

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