Metaphase/anaphase transition and mitotic exit (APC/C-driven)

A taxon-neutral decomposition of the two coupled proteolytic switches that end mitosis. (1) The anaphase-promoting complex/cyclosome (APC/C), a cullin-RING ubiquitin ligase, is activated by CDK1 phosphorylation and by binding of its substrate-adaptor coactivator Cdc20 (Slp1). (2) Until every kinetochore is attached, the spindle assembly checkpoint (SAC) - Mps1/Mph1 kinase at unattached kinetochores, Mad1-Mad2 templating, and the Bub1/Bub3 scaffold - assembles the mitotic checkpoint complex (Mad2-BubR1/Mad3-Bub3-Cdc20) that sequesters and inhibits APC/C-Cdc20. (3) Once the SAC is satisfied, APC/C-Cdc20 ubiquitinates securin (PTTG1, Pds1, Cut2), releasing separase (ESPL1, Esp1, Cut1) to cleave the cohesin kleisin subunit (RAD21, Scc1/Mcd1, Rad21) and trigger sister-chromatid separation, the metaphase/anaphase transition proper. (4) APC/C-Cdc20 and then APC/C-Cdh1 (FZR1, Hct1/Cdh1, Ste9/Srw1) ubiquitinate the mitotic cyclins, extinguishing CDK1 activity. (5) A CDK-counteracting phosphatase - Cdc14 released by the mitotic exit network in budding yeast, Clp1/Flp1 and the septation initiation network in fission yeast, and reactivated PP2A-B55 in metazoa - reverses CDK phosphorylation to complete mitotic exit and reset G1. Representative members are drawn from human, Saccharomyces cerevisiae and Schizosaccharomyces pombe. Grounded in GO:0007091 (metaphase/anaphase transition of mitotic cell cycle) and GO:0010458 (exit from mitosis).

MODULE:metaphase_anaphase_transition_and_mitotic_exitDRAFTCONCRETEBiological Processmodules/metaphase_anaphase_transition_and_mitotic_exit.yaml
metaphase/anaphase transition of mitotic cell cycleGO:0007091 exit from mitosisGO:0010458
GO:0007091
metaphase/anaphase transition of mitotic cell cycle
The module's first half is grounded in the GO term for the mitotic metaphase/anaphase transition.
GO:0010458
exit from mitosis
The module's second half is grounded in the GO term for exit from mitosis.
GO:0031145
anaphase-promoting complex-dependent catabolic process
Both switches are executed by APC/C-dependent ubiquitin-mediated proteolysis.
PMID:7787245
The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis
Identification of the cyclosome (APC/C) as the cyclin-selective ubiquitin ligase active at the end of mitosis.
PMID:7736580
A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B
The CDC27/CDC16-containing 20S complex is the mitotic cyclin B ubiquitin ligase.
PMID:16896351
The anaphase promoting complex/cyclosome: a machine designed to destroy
Review of APC/C composition, coactivators, substrate recognition and its two mitotic switches.
PMID:29167309
Visualizing the complex functions and mechanisms of the anaphase promoting complex/cyclosome (APC/C)
Structural review of the APC/C, its Cdc20/Cdh1 coactivators and MCC inhibition.
PMID:27120157
Molecular mechanism of APC/C activation by mitotic phosphorylation
CDK1/PLK1 phosphorylation of APC/C relieves autoinhibition and permits Cdc20 binding.
PMID:10465783
Whose end is destruction: cell division and the anaphase-promoting complex
Review of APC/C-Cdc20 and APC/C-Cdh1 roles in anaphase onset and mitotic exit.
PMID:9334304
CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis
Cdc20 and Cdh1 are substrate-specific activators of APC/C; Cdc20 targets Pds1 and Cdh1 targets Clb2.
PMID:9288748
Yeast Hct1 is a regulator of Clb2 cyclin proteolysis
Hct1/Cdh1 is required for Clb2 cyclin proteolysis at the end of mitosis.
PMID:9571240
Fission yeast Ste9, a homolog of Hct1/Cdh1 and Fizzy-related, is a novel negative regulator of cell cycle progression during G1-phase
Ste9/Srw1 is the fission-yeast Cdh1 ortholog acting in G1.
PMID:10921876
APC(ste9/srw1) promotes degradation of mitotic cyclins in G(1) and is inhibited by cdc2 phosphorylation
APC/C-Ste9 degrades mitotic cyclins in G1 and is inhibited by Cdc2 phosphorylation.
PMID:26485365
The Molecular Biology of Spindle Assembly Checkpoint Signaling Dynamics
Review of SAC signalling from Mps1 kinetochore recruitment to MCC assembly and APC/C-Cdc20 inhibition.
PMID:34210579
Spindle assembly checkpoint activation and silencing at kinetochores
Review of the kinetochore events that activate and silence the SAC.
PMID:11535616
Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2
The mitotic checkpoint complex (BUBR1-BUB3-CDC20-MAD2) is the APC/C inhibitor produced by the SAC.
PMID:22437499
Structure of the mitotic checkpoint complex
Crystal structure of the fission-yeast MCC (Mad2-Mad3-Slp1/Cdc20) showing how Mad2 and Mad3 block Cdc20 substrate recognition.
PMID:1651172
Feedback control of mitosis in budding yeast
Identification of the MAD genes that arrest cells in mitosis when the spindle is disrupted.
PMID:9635435
An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast
Separase Esp1 is held in a complex with securin Pds1; Pds1 destruction releases Esp1 to dissolve cohesion.
PMID:10403247
Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1
Separase cleaves the cohesin kleisin Scc1 at anaphase onset.
PMID:11509732
Cohesin cleavage by separase required for anaphase and cytokinesis in human cells
Separase cleavage of RAD21/SCC1 is required for anaphase in human cells.
PMID:8632802
Cut2 proteolysis required for sister-chromatid seperation in fission yeast
APC/C-dependent Cut2 (securin) proteolysis is required for sister-chromatid separation in fission yeast.
PMID:8978688
Fission yeast Cut1 and Cut2 are essential for sister chromatid separation, concentrate along the metaphase spindle and form large complexes
Cut1 (separase) and Cut2 (securin) form a complex essential for sister chromatid separation.
PMID:9885559
The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation
Cdc14 triggers mitotic exit by dephosphorylating Cdk substrates including Cdh1, Sic1 and Swi5.
PMID:10219244
Exit from mitosis is triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex
The mitotic exit network GTPase Tem1 triggers release of Cdc14 from its nucleolar Net1/Cfi1 anchor.
PMID:10235265
Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus
Net1/Cfi1 sequesters Cdc14 in the nucleolus until anaphase.
PMID:15568976
Closing mitosis: the functions of the Cdc14 phosphatase and its regulation
Review of Cdc14 regulation by the FEAR and MEN networks and its roles in mitotic exit.
PMID:11715048
Men and sin: what's the difference?
Review comparing the budding-yeast mitotic exit network with the fission-yeast septation initiation network.
PMID:11448769
Fission yeast Clp1p phosphatase regulates G2/M transition and coordination of cytokinesis with cell cycle progression
Clp1/Flp1 is the fission-yeast Cdc14 ortholog, released from the nucleolus at mitosis and acting with the SIN.
PMID:17912263
Finishing mitosis, one step at a time
Review of the ordered dephosphorylation and proteolysis events that constitute mitotic exit across eukaryotes.
PMID:21164013
Greatwall phosphorylates an inhibitor of protein phosphatase 2A that is essential for mitosis
PP2A-B55 is the principal CDK1-counteracting phosphatase whose Greatwall-ENSA inhibition must be reversed for mitotic exit in metazoa.
PMID:19144818
Mitotic exit in the absence of separase activity
Mitotic exit can proceed without separase activity in budding yeast, separating the exit switch from the anaphase switch.

Boundary decisions. The module starts with the assembled, CDK1-phosphorylated APC/C at metaphase and ends with CDK-substrate dephosphorylation and cyclin clearance in telophase/G1. Anaphase chromosome movement, spindle elongation, and cytokinesis are separate modules; the SAC is modeled only as the regulatory restraint on APC/C-Cdc20 (kinetochore-microtubule attachment sensing is not decomposed). The cohesin kleisin is included as an annoton because its cleavage is the metaphase/anaphase transition; cohesin loading and cohesion establishment are separate modules. The securin descriptor has no PANTHER family term: PTTG1 and Cut2 are classified in PTHR10418 but budding-yeast Pds1 is unclassified, so securin grounds through representative members only. Likewise the effector phosphatase step is a taxon variant set: Cdc14 (via the mitotic exit network) is essential for exit in budding yeast, Clp1/Flp1 (via the septation initiation network) contributes in fission yeast, and in metazoa CDC14A/B are dispensable and reactivated PP2A-B55 (and PP1) perform the bulk CDK-substrate dephosphorylation. Deep research: no module deep-research report accompanies this file (no provider credentials were available in the authoring session; hand-writing one under a provider name is prohibited). Open questions: the identity of the metazoan Cdc14-equivalent for specific late-mitotic substrates; the degree to which Cdc20 versus Cdh1 handles cyclin B clearance in each lineage; and whether separase autocleavage and its cyclin B1 binding are best modeled as parts of this module or as regulatory context.

9Nodes
5Parts
1Variant Sets
3Variants
14Annotons
13Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:metaphase_anaphase_transition_and_mitotic_exit deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • securin_separase_cohesin → cyclin_destruction [NOT_CHECKED]
    Temporal ordering of two proteolytic switches.

Gene-review completeness (46/46 grounded genes reviewed)

42 complete review(s) · 39 with deep research · 0 missing review · 7 reviewed but lacking deep research

Gene Review Complete Deep research
ANAPC11 Q9NYG5 ✓ ✓ ✓
ANAPC2 Q9UJX6 ✓ ✓ ✓
APC11 Q12157 ✓ ✓ ✓
apc11 Q9UT86 ✓ ✓ ✓
APC2 Q12440 ✓ ✓ ✓
apc2 Q874R3 ✓ ✓ ✓
BUB1B O60566 ✓ 118/119 ✓
bub3 O42860 ✓ ✓ ✓
BUB3 O43684 ✓ ✓ ✓
BUB3 P26449 ✓ ✓ ✓
CCNB1 P14635 ✓ ✓ ✓
cdc13 P10815 ✓ ✓ ✗
CDC14 Q00684 ✓ ✓ ✓
CDC16 P09798 ✓ ✓ ✓
CDC20 P26309 ✓ ✓ ✓
CDC20 Q12834 ✓ ✓ ✓
CDC27 P30260 ✓ ✓ ✓
CDH1 P53197 ✓ ✓ ✓
CLB2 P24869 ✓ ✓ ✓
clp1 Q9P7H1 ✓ 74/75 ✓
cut1 P18296 ✓ ✓ ✗
cut2 P21135 ✓ ✓ ✗
cut9 P41889 ✓ ✓ ✓
ESP1 Q03018 ✓ ✓ ✓
ESPL1 Q14674 ✓ ✓ ✓
FZR1 Q9UM11 ✓ ✓ ✓
mad2 O14417 ✓ ✓ ✗
MAD2 P40958 ✓ ✓ ✓
MAD2L1 Q13257 ✓ ✓ ✓
mad3 O59767 ✓ ✓ ✓
MAD3 P47074 ✓ ✓ ✓
MCD1 Q12158 ✓ ✓ ✓
mph1 O94235 ✓ ✓ ✗
MPS1 P54199 ✓ ✓ ✓
nuc2 P10505 ✓ ✓ ✓
PDS1 P40316 ✓ ✓ ✓
PPP2CA P67775 ✓ ✓ ✓
PPP2R2A P63151 ✓ ✓ ✓
PTTG1 O95997 ✓ ✓ ✓
RAD21 O60216 ✓ ✓ ✓
rad21 P30776 ✓ 38/40 ✗
slp1 P78972 ✓ ✓ ✗
spg1 P87027 ✓ ✓ ✓
ste9 O13286 ✓ ✓ ✓
TEM1 P38987 ✓ ✓ ✓
TTK P33981 ✓ 34/35 ✓

Details

Context
EukaryotaNCBITaxon:2759
nucleusGO:0005634
Metaphase/anaphase transition and mitotic exitBiological Processmetaphase_anaphase_transition_and_mitotic_exit

SAC-gated APC/C-Cdc20 activation destroys securin to release separase and cleave cohesin; APC/C-Cdc20 then APC/C-Cdh1 destroy mitotic cyclins, and a CDK-counteracting phosphatase resets the G1 state.

metaphase/anaphase transition of mitotic cell cycleGO:0007091 exit from mitosisGO:0010458
Context
EukaryotaNCBITaxon:2759
nucleusGO:0005634

Connections

sac_restraint -> apc_cdc20_activation Negatively Regulates
The MCC sequesters Cdc20 and inhibits APC/C-Cdc20 until all kinetochores are attached.
APC/C-Cdc20 ubiquitinates securin, releasing separase to cleave cohesin.
APC/C-Cdc20 initiates mitotic cyclin ubiquitination; APC/C-Cdh1 completes it.
Sister-chromatid separation (anaphase onset) precedes the bulk of cyclin B destruction and CDK1 inactivation.
Loss of CDK1 activity permits the mitotic-exit phosphatase to be released or reactivated and to reverse CDK substrate phosphorylation.
Dephosphorylation of Cdh1 activates APC/C-Cdh1, reinforcing cyclin clearance (positive feedback).
Part 1: APC/C-Cdc20 ubiquitin ligase activation
APC/C-Cdc20 ubiquitin ligase activationRegulatory Stepapc_cdc20_activation

Cyclin B-CDK1 (and Polo kinase) phosphorylation of APC/C subunits relieves autoinhibition and permits binding of the WD40 coactivator Cdc20, which recruits D-box/KEN-box substrates and stimulates the APC2-APC11 cullin-RING catalytic module.

Annotons

Anaphase-promoting complex/cyclosome
apc_c
Participant: Protein Complex: Anaphase-promoting complex/cyclosome (APC/C)
Protein Complex:
Anaphase-promoting complex/cyclosome (APC/C)GO:0005680
Active units:
APC2 cullin-like scaffold
Participant: Family: APC2 cullin-like subunit (ANAPC2, Apc2, Apc2)
Family:
APC2 cullin-like subunit (ANAPC2, Apc2, Apc2)PANTHER:PTHR45957
Representative Members: ANAPC2UniProtKB:Q9UJX6 Apc2UniProtKB:Q12440 apc2UniProtKB:Q874R3
Role: cullin-like scaffold of the catalytic module
APC11 RING subunit
Participant: Family: APC11 RING-box subunit (ANAPC11, Apc11, Apc11)
Family:
APC11 RING-box subunit (ANAPC11, Apc11, Apc11)PANTHER:PTHR11210
Representative Members: ANAPC11UniProtKB:Q9NYG5 Apc11UniProtKB:Q12157 apc11UniProtKB:Q9UT86
Role: RING subunit that recruits the ubiquitin-charged E2 (UBE2C/UBE2S, Ubc4/Ubc11)
TPR-subunit platform (CDC27/CDC16/CDC23)
Participant: Family: APC/C TPR subunits (CDC27/Apc3, CDC16/Apc6, CDC23/Apc8; Nuc2, Cut9)
Family:
APC/C TPR subunits (CDC27/Apc3, CDC16/Apc6, CDC23/Apc8; Nuc2, Cut9)PANTHER:PTHR12558
Representative Members: CDC27UniProtKB:P30260 Cdc16UniProtKB:P09798 nuc2UniProtKB:P10505 cut9UniProtKB:P41889
Role: tetratricopeptide-repeat scaffold that binds the coactivator C-terminal IR tail

Function

ubiquitin protein ligase activityGO:0061630
Targets: securin mitotic cyclins (cyclin B, cyclin A)

Processes

anaphase-promoting complex-dependent catabolic processGO:0031145

Locations

nucleusGO:0005634

The cullin-RING E3 that executes both mitotic switches; activated by CDK1/PLK1 phosphorylation and by coactivator binding.

PMID:7787245
The cyclosome is the cyclin-selective ubiquitin ligase active at the end of mitosis.
PMID:7736580
A CDC27/CDC16-containing 20S complex ubiquitinates cyclin B.
PMID:27120157
Mitotic phosphorylation of APC/C relieves autoinhibition and enables Cdc20 binding.
Cdc20/Slp1 coactivator
cdc20_coactivator
Participant: Family: Cdc20 APC/C coactivator (CDC20, Cdc20, Slp1)
Family:
Cdc20 APC/C coactivator (CDC20, Cdc20, Slp1)PANTHER:PTHR19918
Representative Members: CDC20UniProtKB:Q12834 Cdc20UniProtKB:P26309 slp1UniProtKB:P78972

Function

ubiquitin ligase activator activityGO:1990757
Targets: D-box/KEN-box substrates (securin, cyclin B)

Processes

positive regulation of mitotic metaphase/anaphase transitionGO:0045842

WD40 coactivator that recruits securin and cyclin B to APC/C and stimulates its ligase activity; the direct target of the SAC.

PMID:9334304
Cdc20 is the substrate-specific APC/C activator for Pds1 (securin).

Connections

cdc20_coactivator -> apc_c Positively Regulates
Cdc20 binding activates APC/C and delivers D-box/KEN-box substrates.
Part 2: spindle assembly checkpoint restraint (optional)
Spindle assembly checkpoint inhibition of APC/C-Cdc20Regulatory Stepsac_restraint

Unattached kinetochores recruit the Mps1/Mph1 kinase, which phosphorylates KNL1/Spc7 MELT motifs to recruit Bub3-Bub1 and Mad1-Mad2; Mad1-bound closed Mad2 templates the conversion of open Mad2 into Cdc20-bound closed Mad2, which with BubR1/Mad3 and Bub3 forms the mitotic checkpoint complex (MCC) that binds and inhibits APC/C-Cdc20 until biorientation is complete.

Annotons

Mps1/Mph1 checkpoint kinase
mps1_kinase
Participant: Family: Mps1 kinase (TTK, Mps1, Mph1)
Family:
Mps1 kinase (TTK, Mps1, Mph1)PANTHER:PTHR22974 PANTHER family name is dominated by other members.
Representative Members: TTKUniProtKB:P33981 Mps1UniProtKB:P54199 mph1UniProtKB:O94235

Function

protein serine/threonine kinase activityGO:0004674
Targets: KNL1/Spc7 MELT motifs; Mad1; Bub1

Processes

mitotic spindle assembly checkpoint signalingGO:0007094

Locations

kinetochoreGO:0000776

Apical kinase whose kinetochore recruitment initiates SAC signalling.

Mitotic checkpoint complex (MCC)
mcc
Participant: Protein Complex: Mitotic checkpoint complex (Mad2-BubR1/Mad3-Bub3-Cdc20)
Protein Complex:
Mitotic checkpoint complex (Mad2-BubR1/Mad3-Bub3-Cdc20)GO:0033597
Active units:
Closed Mad2
Participant: Family: Mad2 (MAD2L1, Mad2, Mad2)
Family:
Mad2 (MAD2L1, Mad2, Mad2)PANTHER:PTHR11842
Representative Members: MAD2L1UniProtKB:Q13257 Mad2UniProtKB:P40958 mad2UniProtKB:O14417
Role: Cdc20-binding HORMA-domain subunit generated by Mad1-Mad2 templating
BubR1/Mad3
Participant: Family: BubR1/Mad3 (BUB1B, Mad3, Mad3)
Family:
BubR1/Mad3 (BUB1B, Mad3, Mad3)PANTHER:PTHR14030
Representative Members: BUB1BUniProtKB:O60566 Mad3UniProtKB:P47074 mad3UniProtKB:O59767
Role: pseudokinase/KEN-box subunit that blocks Cdc20 substrate-binding sites
Bub3
Participant: Family: Bub3 (BUB3, Bub3, Bub3)
Family:
Bub3 (BUB3, Bub3, Bub3)PANTHER:PTHR10971
Representative Members: BUB3UniProtKB:O43684 Bub3UniProtKB:P26449 bub3UniProtKB:O42860
Role: WD40 subunit bridging BubR1/Mad3 to kinetochores and Cdc20

Function

ubiquitin ligase inhibitor activityGO:1990948
Targets: APC/C-Cdc20

Processes

mitotic spindle assembly checkpoint signalingGO:0007094 negative regulation of mitotic metaphase/anaphase transitionGO:0045841

Diffusible wait-anaphase signal that sequesters Cdc20 and occupies the APC/C substrate-binding site until every kinetochore is attached.

PMID:11535616
The BUBR1-BUB3-CDC20-MAD2 complex mediates checkpoint inhibition of APC/C.
PMID:22437499
Structure of the MCC shows Mad2 and Mad3 jointly blocking Cdc20.
PMID:1651172
MAD genes mediate the feedback control that arrests mitosis on spindle damage.

Connections

mps1_kinase -> mcc Causes
Mps1 phosphorylation of kinetochore scaffolds drives Mad1-Mad2 and Bub1-Bub3 recruitment and MCC assembly.
Part 3: securin destruction, separase activation and cohesin cleavage
Securin destruction, separase activation and cohesin cleavageRegulatory Stepsecurin_separase_cohesin

APC/C-Cdc20 ubiquitinates securin; its proteasomal destruction frees the caspase-like protease separase, which cleaves the cohesin kleisin subunit at two sites, dissolving sister-chromatid cohesion and triggering anaphase.

Annotons

Securin
securin
Participant: Family: Securin (PTTG1, Pds1, Cut2)
Family:
Securin (PTTG1, Pds1, Cut2) No PANTHER family term is asserted: PTTG1 and Cut2 are placed in PTHR10418 but budding-yeast Pds1 is unclassified. All three are short, intrinsically disordered separase inhibitors/chaperones with N-terminal D-box/KEN-box degrons.
Representative Members: PTTG1UniProtKB:O95997 Pds1UniProtKB:P40316 cut2UniProtKB:P21135

Function

cysteine-type endopeptidase inhibitor activityGO:0004869
Targets: separase

Processes

negative regulation of mitotic sister chromatid separationGO:2000816

Locations

nucleusGO:0005634

Pseudosubstrate inhibitor and folding chaperone of separase whose APC/C-Cdc20-dependent destruction is the anaphase trigger.

PMID:9635435
Pds1 holds Esp1 in an inhibitory complex until the metaphase/anaphase transition.
PMID:8632802
Cut2 proteolysis is required for sister-chromatid separation.
Separase
separase
Participant: Family: Separase (ESPL1, Esp1, Cut1)
Family:
Separase (ESPL1, Esp1, Cut1)PANTHER:PTHR12792
Representative Members: ESPL1UniProtKB:Q14674 Esp1UniProtKB:Q03018 cut1UniProtKB:P18296

Function

cysteine-type endopeptidase activityGO:0004197
Targets: cohesin kleisin (RAD21/Scc1/Rad21)

Processes

mitotic sister chromatid separationGO:0051306

Locations

nucleusGO:0005634

Caspase-like protease that, once freed from securin (and, in metazoa, from cyclin B-CDK1 inhibition), cleaves the cohesin kleisin to dissolve cohesion.

PMID:10403247
Separase cleaves Scc1 at anaphase onset.
PMID:11509732
Separase cleavage of cohesin is required for anaphase in human cells.
PMID:8978688
Cut1 and Cut2 form a complex essential for sister chromatid separation.
Cohesin kleisin subunit (separase substrate)
cohesin_kleisin
Participant: Family: Cohesin alpha-kleisin (RAD21, Scc1/Mcd1, Rad21)
Family:
Cohesin alpha-kleisin (RAD21, Scc1/Mcd1, Rad21)PANTHER:PTHR12585
Representative Members: RAD21UniProtKB:O60216 Scc1 (Mcd1)UniProtKB:Q12158 rad21UniProtKB:P30776

Function

protein-macromolecule adaptor activityGO:0030674

Processes

mitotic sister chromatid cohesionGO:0007064

Locations

chromatinGO:0000785

Kleisin that closes the cohesin ring around sister chromatids; its separase cleavage opens the ring and constitutes the anaphase transition.

Connections

securin -> separase Negatively Regulates
Securin binds and inhibits separase until its APC/C-Cdc20-dependent destruction.
Separase cleaves the kleisin at its two conserved sites, opening the cohesin ring.
Part 4: mitotic cyclin destruction
APC/C-Cdc20 and APC/C-Cdh1 destruction of mitotic cyclinsRegulatory Stepcyclin_destruction

APC/C-Cdc20 begins cyclin B (and cyclin A) ubiquitination at anaphase onset; as CDK1 activity falls, the second coactivator Cdh1 (FZR1, Hct1/Cdh1, Ste9/Srw1) is dephosphorylated, binds APC/C, and completes cyclin clearance through telophase and G1, keeping CDK activity low until the next Start.

Annotons

Mitotic cyclin (APC/C substrate)
mitotic_cyclin_target
Participant: Family: Mitotic B-type cyclin (cyclin B1, Clb2, Cdc13)
Family:
Mitotic B-type cyclin (cyclin B1, Clb2, Cdc13)PANTHER:PTHR10177
Representative Members: CCNB1UniProtKB:P14635 Clb2UniProtKB:P24869 cdc13UniProtKB:P10815

Function

cyclin-dependent protein serine/threonine kinase activator activityGO:0061575

The CDK1 activator whose D-box-dependent destruction by APC/C terminates mitotic CDK activity.

PMID:7787245
The cyclosome targets cyclins for destruction at the end of mitosis.
Cdh1/Hct1/Ste9 coactivator
cdh1_coactivator
Participant: Family: Cdh1 APC/C coactivator (FZR1, Hct1/Cdh1, Ste9/Srw1)
Family:
Cdh1 APC/C coactivator (FZR1, Hct1/Cdh1, Ste9/Srw1)PANTHER:PTHR19918:SF1
Representative Members: FZR1UniProtKB:Q9UM11 Cdh1 (Hct1)UniProtKB:P53197 ste9 (srw1)UniProtKB:O13286

Function

ubiquitin ligase activator activityGO:1990757
Targets: mitotic cyclins, Polo kinase, Cdc20

Processes

anaphase-promoting complex-dependent catabolic processGO:0031145 exit from mitosisGO:0010458

Late-mitotic/G1 coactivator that is inhibited by CDK phosphorylation and therefore engages only once CDK1 activity has begun to fall, completing cyclin clearance.

PMID:9334304
Cdh1 is the substrate-specific APC/C activator for Clb2.
PMID:9288748
Hct1 is required for Clb2 proteolysis.
PMID:10921876
APC/C-Ste9 degrades mitotic cyclins in G1 and is inhibited by Cdc2 phosphorylation.

Connections

APC/C-Cdh1 recognises the cyclin D-box/KEN-box and completes its ubiquitination.
Part 5: reversal of CDK phosphorylation
CDK-counteracting phosphatase activation (mitotic exit)Regulatory Stepcdk_substrate_dephosphorylation

Falling CDK1 activity is converted into net dephosphorylation of CDK substrates by a phosphatase that is released or reactivated at anaphase. The identity of the dominant phosphatase and of its release network is lineage-specific and is modeled as a taxon variant set.

Variant set: Mitotic-exit phosphatase and its release network by taxon (Exactly One)
Budding-yeast Cdc14 released by the mitotic exit networkRegulatory Stepbudding_yeast_men_cdc14

Cdc14 is held in the nucleolus by Net1/Cfi1; the FEAR network (separase-dependent) gives a transient release at early anaphase and the mitotic exit network (Tem1 GTPase -> Cdc15 -> Dbf2-Mob1) drives sustained release, after which Cdc14 dephosphorylates Cdh1, Sic1 and Swi5 to complete exit.

Context
Saccharomyces cerevisiaeNCBITaxon:4932

Annotons

Cdc14 phosphatase
cdc14_scer
Participant: Family: Cdc14 dual-specificity phosphatase
Family:
Cdc14 dual-specificity phosphatasePANTHER:PTHR23339:SF27
Representative Members: Cdc14UniProtKB:Q00684

Function

protein serine/threonine phosphatase activityGO:0004722
Targets: CDK phosphosites on Cdh1, Sic1, Swi5 and other substrates

Processes

exit from mitosisGO:0010458

Locations

nucleusGO:0005634

The essential mitotic-exit phosphatase of budding yeast.

PMID:9885559
Cdc14 triggers mitotic exit by reversing Cdk-dependent phosphorylation.
PMID:10235265
Cfi1/Net1 anchors Cdc14 in the nucleolus until anaphase.
Tem1 GTPase (mitotic exit network)
men_tem1
Participant: Family: Tem1/Spg1 mitotic-exit GTPase
Family:
Tem1/Spg1 mitotic-exit GTPasePANTHER:PTHR47978:SF24 PANTHER subfamily PTHR47978:SF24 groups the Tem1/Spg1 Ras-superfamily GTPases that sit atop the MEN and SIN.
Representative Members: Tem1UniProtKB:P38987

Function

GTPase activityGO:0003924

Processes

regulation of exit from mitosisGO:0007096

Locations

spindle poleGO:0000922

Spindle-pole-body GTPase whose activation on entry of the daughter-bound pole into the bud triggers the Cdc15 -> Dbf2-Mob1 kinase cascade that releases Cdc14.

PMID:10219244
Tem1-dependent release of Cdc14 from the nucleolar RENT complex triggers exit from mitosis.

Connections

men_tem1 -> cdc14_scer Positively Regulates
The Tem1-initiated MEN cascade releases Cdc14 from Net1.
Fission-yeast Clp1/Flp1 and the septation initiation networkRegulatory Stepfission_yeast_sin_clp1

Clp1/Flp1 leaves the nucleolus at mitotic entry and is kept cytoplasmic by the SIN (Spg1 GTPase -> Cdc7 -> Sid2-Mob1) through anaphase, where it antagonises Cdc2 and couples cytokinesis to mitotic exit; unlike budding-yeast Cdc14 it is not essential for cyclin destruction.

Context
Schizosaccharomyces pombeNCBITaxon:4896

Annotons

Clp1/Flp1 phosphatase
clp1_spom
Participant: Family: Cdc14 dual-specificity phosphatase
Family:
Cdc14 dual-specificity phosphatasePANTHER:PTHR23339:SF27
Representative Members: clp1 (flp1)UniProtKB:Q9P7H1

Function

protein serine/threonine phosphatase activityGO:0004722
Targets: Cdc2 substrates and Cdc25

Processes

exit from mitosisGO:0010458

The fission-yeast Cdc14 ortholog acting with the SIN at mitotic exit.

PMID:11448769
Clp1 regulates G2/M and coordinates cytokinesis with cell cycle progression.
Spg1 GTPase (septation initiation network)
sin_spg1
Participant: Family: Tem1/Spg1 mitotic-exit GTPase
Family:
Tem1/Spg1 mitotic-exit GTPasePANTHER:PTHR47978:SF24
Representative Members: spg1UniProtKB:P87027

Function

GTPase activityGO:0003924

Locations

spindle poleGO:0000922

Spindle-pole-body GTPase atop the SIN (Spg1 -> Cdc7 -> Sid2-Mob1) that keeps Clp1 active and triggers septation.

PMID:11715048
The SIN is the fission-yeast counterpart of the MEN, sharing the Tem1/Spg1 GTPase architecture.

Connections

sin_spg1 -> clp1_spom Positively Regulates
SIN signalling retains Clp1 in the cytoplasm during anaphase.
Metazoan PP2A-B55 reactivationRegulatory Stepmetazoan_pp2a_b55_reactivation

In metazoa CDC14A/B are dispensable for mitotic exit; the bulk reversal of CDK1 phosphorylation is carried out by PP2A-B55 once Greatwall (MASTL) is inactivated and phospho-ENSA/ARPP19 is turned over, together with PP1.

Context
MetazoaNCBITaxon:33208

Annotons

PP2A-B55 mitotic-exit phosphatase
pp2a_b55_exit
Participant: Protein Complex: PP2A-B55 holoenzyme
Protein Complex:
PP2A-B55 holoenzyme
Active units:
PP2A catalytic subunit
Participant: Family: PP2A catalytic subunit
Family:
PP2A catalytic subunitPANTHER:PTHR45619:SF12
Representative Members: PPP2CAUniProtKB:P67775
Role: phosphatase catalytic subunit
B55 regulatory subunit
Participant: Family: PP2A B55 regulatory subunit
Family:
PP2A B55 regulatory subunitPANTHER:PTHR11871:SF2
Representative Members: PPP2R2AUniProtKB:P63151
Role: CDK-substrate-targeting regulatory subunit

Function

protein serine/threonine phosphatase activityGO:0004722
Targets: CDK1 substrates

Processes

exit from mitosisGO:0010458

Principal CDK1-counteracting phosphatase reactivated at anaphase in metazoa.

PMID:21164013
PP2A-B55 inhibition by Greatwall-phosphorylated ENSA is essential for mitosis; its reversal accompanies exit.
PMID:17912263
Ordered dephosphorylation of CDK substrates drives mitotic exit.