G2/M transition of the mitotic cell cycle (mitotic entry)

A taxon-neutral decomposition of mitotic entry, the switch-like activation of cyclin B-CDK1 (Cdc2/Cdc28-Clb2/Cdc13) at the G2/M transition. Five steps are modeled: (1) assembly of the cyclin B-CDK1 holoenzyme and activating T-loop phosphorylation by the CDK-activating kinase (CDK7-cyclin H-MAT1 in metazoa and Mcs6-Mcs2 in fission yeast; the unrelated single-subunit Cak1 in budding yeast); (2) inhibitory phosphorylation of CDK1 Tyr15 (and Thr14) by the Wee1/Mik1/Swe1 and Myt1 kinases, which holds the complex inactive through G2; (3) activating dephosphorylation by the Cdc25 (Mih1) phosphatase, which triggers mitotic entry; (4) the Polo-like kinase (PLK1, Cdc5, Plo1), which reinforces the transition by activating Cdc25 and priming Wee1 for destruction; and (5) the Greatwall-endosulfine axis (MASTL/Rim15/Ppk18 -> ENSA-ARPP19/Igo1-2/Igo1 -| PP2A-B55), which suppresses the CDK-counteracting phosphatase so that CDK substrate phosphorylation can accumulate. Mutual antagonism between CDK1 and Wee1, and positive feedback between CDK1 and Cdc25, make the transition bistable and irreversible. Checkpoint kinases that restrain Cdc25 and activate Wee1 after DNA damage are modeled as an optional regulatory part. Representative members are drawn from human, Saccharomyces cerevisiae and Schizosaccharomyces pombe. Grounded in GO:0000086 (G2/M transition of mitotic cell cycle).

MODULE:g2_m_transitionDRAFTCONCRETEBiological Processmodules/g2_m_transition.yaml
G2/M transition of mitotic cell cycleGO:0000086
GO:0000086
G2/M transition of mitotic cell cycle
The module is grounded in the GO biological process term for the G2/M transition.
PMID:2138713
Universal control mechanism regulating onset of M-phase
Establishes that a cyclin B-cdc2 (CDK1) kinase, activated by tyrosine dephosphorylation, is the universal trigger of M-phase onset in eukaryotes.
PMID:2682257
Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis
Tyr15 phosphorylation of cdc2 is inhibitory and its removal is the rate-limiting event for mitotic entry in fission yeast.
PMID:3032459
Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog
wee1 encodes a protein kinase that negatively regulates mitotic entry.
PMID:1706223
mik1 and wee1 cooperate in the inhibitory tyrosine phosphorylation of cdc2
Wee1 and its paralog Mik1 are the kinases that phosphorylate cdc2 Tyr15 in fission yeast.
PMID:3955656
cdc25+ functions as an inducer in the mitotic control of fission yeast
cdc25 is a dosage-dependent inducer of mitosis that antagonizes wee1.
PMID:1825803
The cdc25 protein controls tyrosine dephosphorylation of the cdc2 protein in a cell-free system
Cdc25 controls the tyrosine dephosphorylation of cdc2 that activates the kinase.
PMID:1655274
The cdc25 protein contains an intrinsic phosphatase activity
Cdc25 is itself the CDK1-Tyr15 phosphatase.
PMID:19364923
The decision to enter mitosis: feedback and redundancy in the mitotic entry network
Review of the mitotic entry network: cyclin B-CDK1, Wee1/Myt1, Cdc25 and PLK1 form feedback loops that make the G2/M switch bistable and robust.
PMID:8069918
A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase
CDK7 with cyclin H constitutes the CDK-activating kinase (CAK) in metazoa.
PMID:8752210
The Cdk-activating kinase (CAK) from budding yeast
Budding yeast uses Cak1, a single-subunit kinase unrelated to CDK7, as its CDK-activating kinase.
PMID:16280550
Secrets of a double agent: CDK7 in cell-cycle control and transcription
Review of CDK7-cyclin H-MAT1 as both the CDK-activating kinase and the TFIIH CTD kinase, and of the Mcs6/Csk1 arrangement in fission yeast.
PMID:8703070
Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts
Polo-like kinase phosphorylates and activates Cdc25 at mitotic entry.
PMID:7744248
The conserved Schizosaccharomyces pombe kinase plo1, required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells
Plo1 is the fission-yeast Polo kinase.
PMID:21164013
Greatwall phosphorylates an inhibitor of protein phosphatase 2A that is essential for mitosis
Greatwall kinase phosphorylates ENSA, converting it into an inhibitor of PP2A-B55 that is essential for mitotic entry and maintenance.
PMID:21164014
The substrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting protein phosphatase 2A
Greatwall-phosphorylated Arpp19 inhibits PP2A-B55, allowing CDK1 substrate phosphorylation to accumulate at mitotic entry.
PMID:11448769
Fission yeast Clp1p phosphatase regulates G2/M transition and coordination of cytokinesis with cell cycle progression
The Cdc14-family phosphatase Clp1 antagonizes mitotic entry in fission yeast by dephosphorylating Cdc25, an example of a CDK-counteracting phosphatase acting at G2/M.
PMID:1165770
Genetic control of cell size at cell division in yeast
wee mutants of fission yeast divide at reduced size, showing that the G2/M control couples growth to division.
PMID:11413462
Mitotic kinases as regulators of cell division and its checkpoints
Review of CDK1, Polo and Aurora kinases in mitotic entry and progression.
PMID:10637286
Regulation of mitotic inhibitor Mik1 helps to enforce the DNA damage checkpoint
Checkpoint signalling upregulates the Wee1 paralog Mik1 to enforce the G2/M DNA-damage delay in fission yeast.
PMID:11298456
The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
Checkpoint kinases phosphorylate Cdc25A to trigger its degradation, an example of checkpoint restraint acting on the Cdc25 phosphatase.

Boundary decisions. The module starts with cyclin B accumulation in G2 and ends with fully active cyclin B-CDK1; the downstream execution of mitosis (nuclear envelope breakdown, spindle assembly, chromosome condensation) and the subsequent metaphase/anaphase transition are separate modules. Cyclin B nuclear import and CDK1-cyclin B centrosomal activation are localisation details recorded in annoton locations rather than as parts. The CAK step is split by taxon because the budding-yeast Cak1 is not a CDK7 ortholog. The Greatwall-endosulfine axis is included as an optional part: it is essential for mitotic entry in metazoa, whereas in fission yeast Ppk18-Igo1-PP2A(Pab1) primarily couples TORC1/nutrient status to mitotic timing and in budding yeast Rim15-Igo1/2-PP2A(Cdc55) is best characterised in quiescence entry, with PP2A-Cdc55 acting on Swe1/Mih1 during mitotic entry. The checkpoint restraint part is optional context for the same reason. The Wee1 annoton spans Wee1-type and Myt1/Mik1-type kinases within one PANTHER family (PTHR11042), whose PANTHER name is dominated by the eIF2-alpha kinases. 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 relative contribution of PP2A-B55 inhibition versus Cdc25 activation to the switch in each lineage; whether Cdc25 activation by PLK1 or by CDK1 feedback is the primary trigger in human somatic cells; and how cell size is read by the Cdr2-Wee1 / Cdc25-scaling systems in fission yeast (recorded in the pombe GO-CAM gomodel:69729a3800001390 but outside this module boundary).

9Nodes
6Parts
1Variant Sets
2Variants
11Annotons
13Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:g2_m_transition 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.

Function consistency and core coverage

31 gene-function check(s) reflected in core functions · 0 conflict(s) · 13 evidence or coverage gap(s) (45 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
cdk1 CDK1
UniProtKB:P06493
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cdk1 Cdc28
UniProtKB:P00546
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cdk1 cdc2
UniProtKB:P04551
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyclin_b CCNB1
UniProtKB:P14635
Family Representative 		cyclin-dependent protein serine/threonine kinase activator activity
GO:0061575 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyclin_b Clb2
UniProtKB:P24869
Family Representative 		cyclin-dependent protein serine/threonine kinase activator activity
GO:0061575 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyclin_b cdc13
UniProtKB:P10815
Family Representative 		cyclin-dependent protein serine/threonine kinase activator activity
GO:0061575 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
cdk7_cak CDK7
UniProtKB:P50613
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cdk7_cak mcs6 (crk1)
UniProtKB:Q12126
Family Representative 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cak1 Cak1
UniProtKB:P43568
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
wee1_kinase WEE1
UniProtKB:P30291
Family Representative 		protein tyrosine kinase activity
GO:0004713 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
wee1_kinase PKMYT1
UniProtKB:Q99640
Family Representative 		protein tyrosine kinase activity
GO:0004713 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
wee1_kinase Swe1
UniProtKB:P32944
Family Representative 		protein tyrosine kinase activity
GO:0004713 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
wee1_kinase wee1
UniProtKB:P07527
Family Representative 		protein tyrosine kinase activity
GO:0004713 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
wee1_kinase mik1
UniProtKB:P30290
Family Representative 		protein tyrosine kinase activity
GO:0004713 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cdc25_phosphatase CDC25C
UniProtKB:P30307
Family Representative 		protein tyrosine phosphatase activity
GO:0004725 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cdc25_phosphatase CDC25B
UniProtKB:P30305
Family Representative 		protein tyrosine phosphatase activity
GO:0004725 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cdc25_phosphatase Mih1
UniProtKB:P23748
Family Representative 		protein tyrosine phosphatase activity
GO:0004725 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cdc25_phosphatase cdc25
UniProtKB:P06652
Family Representative 		protein tyrosine phosphatase activity
GO:0004725 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
polo_kinase PLK1
UniProtKB:P53350
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
polo_kinase Cdc5
UniProtKB:P32562
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
polo_kinase plo1
UniProtKB:P50528
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
greatwall_kinase MASTL
UniProtKB:Q96GX5
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
greatwall_kinase Rim15
UniProtKB:P43565
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
greatwall_kinase ppk18
UniProtKB:Q8TFG6
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
endosulfine ENSA
UniProtKB:O43768
Family Representative 		protein phosphatase inhibitor activity
GO:0004864 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
endosulfine ARPP19
UniProtKB:P56211
Family Representative 		protein phosphatase inhibitor activity
GO:0004864 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
endosulfine Igo1
UniProtKB:P53897
Family Representative 		protein phosphatase inhibitor activity
GO:0004864 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
endosulfine igo1 (mug134)
UniProtKB:P79058
Family Representative 		protein phosphatase inhibitor activity
GO:0004864 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pp2a_b55 PROTEIN_COMPLEX
Gene 		protein serine/threonine phosphatase activity
GO:0004722 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
pp2a_b55/pp2a_catalytic PPP2CA
UniProtKB:P67775
Family Representative 		protein serine/threonine phosphatase activity
GO:0004722 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pp2a_b55/pp2a_catalytic Pph21
UniProtKB:P23594
Family Representative 		protein serine/threonine phosphatase activity
GO:0004722 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pp2a_b55/pp2a_catalytic ppa2
UniProtKB:P23636
Family Representative 		protein serine/threonine phosphatase activity
GO:0004722 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
checkpoint_kinase CHEK1
UniProtKB:O14757
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
checkpoint_kinase chk1
UniProtKB:P34208
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cdk1 Mitotic cyclin-dependent kinase 1 (CDK1, Cdc28, Cdc2)
PANTHER:PTHR24056
Family 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Family Function Unreviewed
Family review leaves GO:0004693 UNRESOLVED. CDK7 assays and cyclin-H/MAT1 regulation support cyclin-dependent kinase activity; CDK1 and CDK2 supply other positive branches. The inventory also explicitly includes CDKL1, CDKL2, CDKL3, CDKL4 and CDKL5. The present sources do not establish that their kinase reactions require cyclin association, so the cyclin-dependent qualifier is not inferred from the kinase fold or CDK-like name alone. This is a specific unresolved regulatory boundary, not a claim that these proteins lack kinase activity. CDK5 p35/p39 regulation is not used as a negative GO:0004693 counterexample.
cyclin_b Mitotic B-type cyclin (cyclin B1, Clb2, Cdc13)
PANTHER:PTHR10177
Family 		cyclin-dependent protein serine/threonine kinase activator activity
GO:0061575 		Family Function Unreviewed
Family review leaves GO:0016538 UNRESOLVED. Fly CycA contributes to mitotic cell-cycle progression and cyclin-mediated CDK substrate recognition (PMID:2564316; PMID:17431409). The native CycA-PC sequence differs from the reviewed 491-residue form by only Gln66 and retains the entire cyclin domain, supporting kinase regulation for this isoform. The broader family includes cyclins with distinct partners and regulatory outputs; kinase regulation is not intrinsic kinase catalysis. The complete set with direct CDK-regulator activity is unresolved beyond these positively supported branches.
cdk7_cak CDK7-family CDK-activating kinase (CDK7, Mcs6/Crk1)
PANTHER:PTHR24056
Family 		cyclin-dependent protein serine/threonine kinase activity
GO:0004693 		Family Function Unreviewed
Family review leaves GO:0004693 UNRESOLVED. CDK7 assays and cyclin-H/MAT1 regulation support cyclin-dependent kinase activity; CDK1 and CDK2 supply other positive branches. The inventory also explicitly includes CDKL1, CDKL2, CDKL3, CDKL4 and CDKL5. The present sources do not establish that their kinase reactions require cyclin association, so the cyclin-dependent qualifier is not inferred from the kinase fold or CDK-like name alone. This is a specific unresolved regulatory boundary, not a claim that these proteins lack kinase activity. CDK5 p35/p39 regulation is not used as a negative GO:0004693 counterexample.
cak1 Cak1 (Civ1) CDK-activating kinase
PANTHER:PTHR24056
Family 		protein serine/threonine kinase activity
GO:0004674 		Family Function Unreviewed
Family review leaves GO:0004693 UNRESOLVED. CDK7 assays and cyclin-H/MAT1 regulation support cyclin-dependent kinase activity; CDK1 and CDK2 supply other positive branches. The inventory also explicitly includes CDKL1, CDKL2, CDKL3, CDKL4 and CDKL5. The present sources do not establish that their kinase reactions require cyclin association, so the cyclin-dependent qualifier is not inferred from the kinase fold or CDK-like name alone. This is a specific unresolved regulatory boundary, not a claim that these proteins lack kinase activity. CDK5 p35/p39 regulation is not used as a negative GO:0004693 counterexample.
wee1_kinase Wee1-family CDK1 inhibitory kinases (WEE1, PKMYT1, Swe1, Wee1, Mik1)
PANTHER:PTHR11042
Family 		protein tyrosine kinase activity
GO:0004713 		Family Function Unreviewed
Family review leaves GO:0004713 UNRESOLVED. Tyrosine-directed inhibitory CDK phosphorylation is supported for human WEE1 and for pombe Wee1: purified pombe Wee1 directly phosphorylates cyclin-associated Cdc2 on Tyr15 (PMID:1372994). These proteins occupy different PANTHER subfamilies, and additional Wee1-related regulators require the same substrate-level assessment. The broader family also includes eIF2-alpha-directed serine/threonine kinases. Human WEE1 SF72 is therefore a verified positive branch, not the exhaustive boundary of protein tyrosine kinase activity; the complete applicable set remains unresolved.
cdc25_phosphatase Cdc25 dual-specificity phosphatase (CDC25A/B/C, Mih1, Cdc25)
PANTHER:PTHR10828
Family 		protein tyrosine phosphatase activity
GO:0004725 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10828.
polo_kinase Polo-like kinase (PLK1, Cdc5, Plo1)
PANTHER:PTHR24345
Family 		protein serine/threonine kinase activity
GO:0004674 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24345.
greatwall_kinase Greatwall/MASTL kinase (MASTL, Rim15, Ppk18)
PANTHER:PTHR24356:SF1
Family 		protein serine/threonine kinase activity
GO:0004674 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24356:SF1.
endosulfine Endosulfine (ENSA, ARPP19, Igo1/2)
PANTHER:PTHR10358
Family 		protein phosphatase inhibitor activity
GO:0004864 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10358.
pp2a_catalytic PP2A catalytic subunit (PPP2CA, Pph21, Ppa2)
PANTHER:PTHR45619:SF12
Family 		protein serine/threonine phosphatase activity
GO:0004722 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR45619:SF12.
checkpoint_kinase Chk1 effector checkpoint kinase (CHEK1, Chk1)
Family 		protein serine/threonine kinase activity
GO:0004674 		Family Id Missing
The family has no identifier linking it to a curated family review.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

1 negative regulator(s) described as feedback but with no upstream edge (loop cut):

  • cdk1_cyclinb_assembly ⊣ wee1_inhibition [closed]
    cdk1_cyclinb_assembly is regulated by cdc25_activation, greatwall_ensa_pp2a: feedback loop closed
  • polo_reinforcement ⊣ wee1_inhibition [cut]
    polo_reinforcement is described as feedback/induced but has no incoming activating edge: the loop is cut (it reads as a free input in a Boolean translation)
  • checkpoint_restraint ⊣ cdc25_activation [input]
    checkpoint_restraint is a negative regulator with no upstream edge (not described as feedback)
  • endosulfine ⊣ pp2a_b55 [closed]
    endosulfine is regulated by greatwall_kinase: feedback loop closed

Gene-review completeness (36/36 grounded genes reviewed)

32 complete review(s) · 31 with deep research · 0 missing review · 5 reviewed but lacking deep research

Gene Review Complete Deep research
ARPP19 P56211 ✓ ✓ ✓
CAK1 P43568 ✓ ✓ ✓
CCNB1 P14635 ✓ ✓ ✓
cdc13 P10815 ✓ ✓ ✗
cdc2 P04551 ✓ ✓ ✗
cdc25 P06652 ✓ ✓ ✗
CDC25B P30305 ✓ 56/57 ✓
CDC25C P30307 ✓ ✓ ✓
CDC28 P00546 ✓ ✓ ✓
CDC5 P32562 ✓ ✓ ✓
CDC55 Q00362 ✓ ✓ ✓
CDK1 P06493 ✓ ✓ ✓
CDK7 P50613 ✓ ✓ ✓
CHEK1 O14757 ✓ ✓ ✓
chk1 P34208 ✓ 39/40 ✗
CLB2 P24869 ✓ ✓ ✓
ENSA O43768 ✓ ✓ ✓
IGO1 P53897 ✓ ✓ ✓
igo1 P79058 ✓ ✓ ✓
MASTL Q96GX5 ✓ ✓ ✓
mcs6 Q12126 ✓ ✓ ✓
MIH1 P23748 ✓ ✓ ✓
mik1 P30290 ✓ ✓ ✓
pab1 Q12702 ✓ ✓ ✓
PKMYT1 Q99640 ✓ ✓ ✓
PLK1 P53350 ✓ 326/328 ✓
plo1 P50528 ✓ ✓ ✓
ppa2 P23636 ✓ ✓ ✓
PPH21 P23594 ✓ ✓ ✓
ppk18 Q8TFG6 ✓ ✓ ✓
PPP2CA P67775 ✓ ✓ ✓
PPP2R2A P63151 ✓ ✓ ✓
RIM15 P43565 ✓ ✓ ✓
SWE1 P32944 ✓ ✓ ✓
wee1 P07527 ✓ ✓ ✗
WEE1 P30291 ✓ 45/46 ✓

Details

Context
EukaryotaNCBITaxon:2759
nucleusGO:0005634 cytoplasmGO:0005737
G2/M transition (mitotic entry)Biological Processg2_m_transition

Cyclin B-CDK1 is assembled and T-loop-phosphorylated, held inactive by Wee1/Myt1 Tyr15 phosphorylation, and switched on by Cdc25 with Polo-kinase and Greatwall-endosulfine reinforcement.

G2/M transition of mitotic cell cycleGO:0000086
Context
EukaryotaNCBITaxon:2759
nucleusGO:0005634 cytoplasmGO:0005737

Connections

cdk1_cyclinb_assembly -> wee1_inhibition Provides Input For
The assembled, T-loop-phosphorylated cyclin B-CDK1 is the substrate that Wee1/Myt1 hold inactive.
wee1_inhibition -> cdc25_activation Provides Input For
Tyr15/Thr14-phosphorylated CDK1 is the substrate of Cdc25.
cdc25_activation -> cdk1_cyclinb_assembly Positively Regulates
Cdc25 dephosphorylation converts the poised complex into active cyclin B-CDK1.
cdk1_cyclinb_assembly -> cdc25_activation Positively Regulates
Active CDK1 phosphorylates and activates Cdc25 (positive feedback).
cdk1_cyclinb_assembly -> wee1_inhibition Negatively Regulates
Active CDK1 phosphorylates and inactivates Wee1, priming its destruction (double-negative feedback).
polo_reinforcement -> cdc25_activation Positively Regulates
Polo kinase phosphorylates and activates Cdc25.
polo_reinforcement -> wee1_inhibition Negatively Regulates
Polo kinase phosphorylation of Wee1 creates the phosphodegron for its SCF-dependent destruction.
CDK1 phosphorylates and activates Greatwall kinase.
Inhibition of PP2A-B55 lets CDK1 substrate phosphorylation and Cdc25/Wee1 phospho-states accumulate.
checkpoint_restraint -> cdc25_activation Negatively Regulates
Checkpoint kinases inactivate, sequester or degrade Cdc25.
checkpoint_restraint -> wee1_inhibition Positively Regulates
Checkpoint signalling stabilises and upregulates Wee1/Mik1.
Part 1: cyclin B-CDK1 holoenzyme assembly and T-loop activation
Cyclin B-CDK1 assembly and CAK phosphorylationRegulatory Stepcdk1_cyclinb_assembly

The mitotic cyclin accumulates through G2, binds CDK1, and the complex is phosphorylated on the CDK1 T-loop (Thr161/Thr167) by the CDK-activating kinase. The resulting complex is competent but is held inactive by inhibitory Tyr15 phosphorylation until Cdc25 acts.

Annotons

CDK1 catalytic subunit
cdk1
Participant: Family: Mitotic cyclin-dependent kinase 1 (CDK1, Cdc28, Cdc2)
Family:
Mitotic cyclin-dependent kinase 1 (CDK1, Cdc28, Cdc2)PANTHER:PTHR24056
Representative Members: CDK1UniProtKB:P06493 Cdc28UniProtKB:P00546 cdc2UniProtKB:P04551

Function

cyclin-dependent protein serine/threonine kinase activityGO:0004693
Targets: mitotic substrates (lamins, condensin, Cdc25, Wee1, Greatwall)

Processes

G2/M transition of mitotic cell cycleGO:0000086

Locations

nucleusGO:0005634

Catalytic subunit of M-phase promoting factor; its activation state is the output of the module.

PMID:2138713
Cyclin B-cdc2 kinase activation is the universal M-phase trigger.
Mitotic cyclin B regulatory subunit
cyclin_b
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

Locations

cytoplasmGO:0005737 nucleusGO:0005634

Accumulates through G2 and is the rate-limiting activator of CDK1; its later APC/C-mediated destruction ends mitosis.

Variant set: CDK-activating kinase by taxon (Exactly One)
CDK7-cyclin H-MAT1 / Mcs6-Mcs2 CAKReactioncak_cdk7_cyclinh

In metazoa and fission yeast the CAK is a CDK7-family kinase (CDK7; Mcs6/Crk1) with its cyclin H (cyclin H; Mcs2) and, in metazoa, the assembly factor MAT1.

Annotons

CDK7/Mcs6 CDK-activating kinase
cdk7_cak
Participant: Family: CDK7-family CDK-activating kinase (CDK7, Mcs6/Crk1)
Family:
CDK7-family CDK-activating kinase (CDK7, Mcs6/Crk1)PANTHER:PTHR24056
Representative Members: CDK7UniProtKB:P50613 mcs6 (crk1)UniProtKB:Q12126

Function

cyclin-dependent protein serine/threonine kinase activityGO:0004693
Targets: CDK1 T-loop (Thr161/Thr167)

Phosphorylates the CDK1 T-loop threonine, a prerequisite for full kinase activity; also the TFIIH CTD kinase.

PMID:8069918
CDK7 with cyclin H forms the CDK-activating kinase.
PMID:16280550
Fission yeast Mcs6-Mcs2 is the CDK7-cyclin H ortholog acting as CAK.
Cak1 single-subunit CAKReactioncak_cak1
Context
Saccharomyces cerevisiaeNCBITaxon:4932

Annotons

Cak1 CDK-activating kinase
cak1
Participant: Family: Cak1 (Civ1) CDK-activating kinase
Family:
Cak1 (Civ1) CDK-activating kinasePANTHER:PTHR24056 A monomeric kinase that is not a CDK7 ortholog yet serves as the sole CAK for Cdc28 in budding yeast. The local PANTHER 19.0 classification places Cak1 in the CDK family PTHR24056 (subfamily SF508), whereas the UniProt cross-reference assigns PTHR44167; the module follows the local classification.
Representative Members: Cak1UniProtKB:P43568

Function

protein serine/threonine kinase activityGO:0004674
Targets: Cdc28 T-loop (Thr169)

Phosphorylates the Cdc28 T-loop; cyclin-independent.

PMID:8752210
Cak1 is the budding-yeast CDK-activating kinase.
Part 2: inhibitory tyrosine phosphorylation
Inhibitory Tyr15/Thr14 phosphorylation by Wee1/Myt1Regulatory Stepwee1_inhibition

Wee1-family kinases (Wee1, Mik1, Swe1) phosphorylate CDK1 Tyr15 and the membrane-associated Myt1 phosphorylates Thr14 and Tyr15, holding the cyclin B-CDK1 complex inactive through G2; their activity is coupled to cell size and to checkpoint signalling.

Annotons

Wee1/Mik1/Myt1 CDK1-inhibitory kinase
wee1_kinase
Participant: Family: Wee1-family CDK1 inhibitory kinases (WEE1, PKMYT1, Swe1, Wee1, Mik1)
Family:
Wee1-family CDK1 inhibitory kinases (WEE1, PKMYT1, Swe1, Wee1, Mik1)PANTHER:PTHR11042 PANTHER family PTHR11042 groups the Wee1/Mik1/Swe1 nuclear tyrosine kinases and the Myt1 dual Thr14/Tyr15 kinase with the eIF2-alpha kinases, which dominate the family name.
Representative Members: WEE1UniProtKB:P30291 PKMYT1UniProtKB:Q99640 Swe1UniProtKB:P32944 wee1UniProtKB:P07527 mik1UniProtKB:P30290

Function

protein tyrosine kinase activityGO:0004713
Targets: CDK1 Tyr15 (and Thr14 for Myt1)

Processes

negative regulation of G2/M transition of mitotic cell cycleGO:0010972

Locations

nucleusGO:0005634

Keeps the assembled cyclin B-CDK1 inactive until the G2/M switch is triggered; is itself phosphorylated and destroyed once CDK1 and PLK1 are active (mutual antagonism).

PMID:3032459
wee1 encodes a protein kinase that negatively regulates mitosis.
PMID:1706223
mik1 and wee1 cooperate in inhibitory tyrosine phosphorylation of cdc2.
PMID:2682257
cdc2 Tyr15 phosphorylation is inhibitory and its removal triggers mitosis.
Part 3: activating dephosphorylation
Cdc25 dephosphorylation of CDK1 Tyr15/Thr14Reactioncdc25_activation

The dual-specificity phosphatase Cdc25 (Mih1 in budding yeast) removes the inhibitory phosphates from CDK1, triggering mitotic entry. Cdc25 is itself activated by CDK1 and PLK1 phosphorylation, creating the positive feedback that makes the switch irreversible.

Annotons

Cdc25 CDK1-activating phosphatase
cdc25_phosphatase
Participant: Family: Cdc25 dual-specificity phosphatase (CDC25A/B/C, Mih1, Cdc25)
Family:
Cdc25 dual-specificity phosphatase (CDC25A/B/C, Mih1, Cdc25)PANTHER:PTHR10828
Representative Members: CDC25CUniProtKB:P30307 CDC25BUniProtKB:P30305 Mih1UniProtKB:P23748 cdc25UniProtKB:P06652

Function

protein tyrosine phosphatase activityGO:0004725
Targets: CDK1 phospho-Tyr15 / phospho-Thr14

Processes

positive regulation of G2/M transition of mitotic cell cycleGO:0010971

Locations

nucleusGO:0005634

Rate-limiting mitotic inducer; its abundance and activation state set the timing of mitotic entry.

PMID:3955656
cdc25 is a dosage-dependent mitotic inducer.
PMID:1825803
Cdc25 controls tyrosine dephosphorylation of cdc2.
PMID:1655274
Cdc25 has intrinsic phosphatase activity.
Part 4: Polo-kinase reinforcement
Polo-like kinase activation of Cdc25 and inhibition of Wee1Regulatory Steppolo_reinforcement

The Polo-like kinase (PLK1, Cdc5, Plo1), activated at the centrosome or spindle pole body in late G2, phosphorylates Cdc25 to activate it and Wee1 to prime its SCF(beta-TrCP)-dependent destruction, amplifying the CDK1 feedback loops.

Annotons

Polo-like kinase
polo_kinase
Participant: Family: Polo-like kinase (PLK1, Cdc5, Plo1)
Family:
Polo-like kinase (PLK1, Cdc5, Plo1)PANTHER:PTHR24345
Representative Members: PLK1UniProtKB:P53350 Cdc5UniProtKB:P32562 plo1UniProtKB:P50528

Function

protein serine/threonine kinase activityGO:0004674
Targets: Cdc25 (activating) Wee1 (degradation priming)

Processes

positive regulation of G2/M transition of mitotic cell cycleGO:0010971

Locations

spindle poleGO:0000922

Feed-forward amplifier of the CDK1 switch acting on both Cdc25 and Wee1.

PMID:8703070
Polo-like kinase Plx1 phosphorylates and activates Cdc25.
PMID:7744248
plo1 is the fission-yeast Polo kinase.
Part 5: suppression of the CDK-counteracting phosphatase (optional)
Greatwall-endosulfine inhibition of PP2A-B55Regulatory Stepgreatwall_ensa_pp2a

Active CDK1 phosphorylates and activates Greatwall kinase (MASTL/Rim15/Ppk18), which phosphorylates the endosulfine proteins (ENSA and ARPP19; Igo1/2; Igo1) so that they bind and inhibit the PP2A-B55 phosphatase that would otherwise reverse CDK1 substrate phosphorylation and Cdc25/Wee1 activation states.

Annotons

Greatwall kinase
greatwall_kinase
Participant: Family: Greatwall/MASTL kinase (MASTL, Rim15, Ppk18)
Family:
Greatwall/MASTL kinase (MASTL, Rim15, Ppk18)PANTHER:PTHR24356:SF1
Representative Members: MASTLUniProtKB:Q96GX5 Rim15UniProtKB:P43565 ppk18UniProtKB:Q8TFG6

Function

protein serine/threonine kinase activityGO:0004674
Targets: endosulfine (ENSA/ARPP19, Igo1/2)

CDK1-activated kinase whose only established mitotic substrates are the endosulfines.

PMID:21164013
Greatwall phosphorylates ENSA to make it a PP2A inhibitor essential for mitosis.
Endosulfine PP2A-B55 inhibitor
endosulfine
Participant: Family: Endosulfine (ENSA, ARPP19, Igo1/2)
Family:
Endosulfine (ENSA, ARPP19, Igo1/2)PANTHER:PTHR10358
Representative Members: ENSAUniProtKB:O43768 ARPP19UniProtKB:P56211 Igo1UniProtKB:P53897 igo1 (mug134)UniProtKB:P79058

Function

protein phosphatase inhibitor activityGO:0004864
Targets: PP2A-B55

Phospho-endosulfine is a high-affinity, slowly turned-over unfair-competitor substrate that occupies PP2A-B55.

PMID:21164014
Greatwall-phosphorylated Arpp19 inhibits PP2A to control mitosis.
PP2A-B55 CDK-counteracting phosphatase
pp2a_b55
Participant: Protein Complex: PP2A-B55 holoenzyme (PP2A catalytic + B55 regulatory subunit)
Protein Complex:
PP2A-B55 holoenzyme (PP2A catalytic + B55 regulatory subunit)
Active units:
PP2A catalytic subunit
Participant: Family: PP2A catalytic subunit (PPP2CA, Pph21, Ppa2)
Family:
PP2A catalytic subunit (PPP2CA, Pph21, Ppa2)PANTHER:PTHR45619:SF12
Representative Members: PPP2CAUniProtKB:P67775 Pph21UniProtKB:P23594 ppa2UniProtKB:P23636
Role: phosphatase catalytic subunit
Function:
protein serine/threonine phosphatase activityGO:0004722
B55 regulatory subunit
Participant: Family: PP2A B55 regulatory subunit (PPP2R2A, Cdc55, Pab1)
Family:
PP2A B55 regulatory subunit (PPP2R2A, Cdc55, Pab1)PANTHER:PTHR11871
Representative Members: PPP2R2AUniProtKB:P63151 Cdc55UniProtKB:Q00362 pab1UniProtKB:Q12702
Role: substrate-targeting regulatory subunit that confers CDK-substrate preference

Function

protein serine/threonine phosphatase activityGO:0004722
Targets: CDK1 substrates; Cdc25 and Wee1 phosphosites

Processes

negative regulation of G2/M transition of mitotic cell cycleGO:0010972

The principal phosphatase opposing CDK1 in interphase; its inhibition is required for the phospho-state switch at G2/M and its reactivation drives mitotic exit.

Connections

Greatwall phosphorylates endosulfine on the conserved serine that creates the PP2A-B55-binding form.
endosulfine -> pp2a_b55 Negatively Regulates
Phospho-endosulfine binds and inhibits PP2A-B55.
Part 6: checkpoint restraint (optional)
Checkpoint kinase restraint of Cdc25 and activation of Wee1Regulatory Stepcheckpoint_restraint

On DNA damage or incomplete replication, the effector checkpoint kinases (Chk1/Chk2; Chk1/Cds1 in fission yeast; Rad53/Chk1 in budding yeast) phosphorylate Cdc25 to inactivate, sequester (14-3-3) or degrade it and stabilise Wee1/Mik1, delaying mitotic entry.

Annotons

Effector checkpoint kinase (Chk1)
checkpoint_kinase
Participant: Family: Chk1 effector checkpoint kinase (CHEK1, Chk1)
Family:
Chk1 effector checkpoint kinase (CHEK1, Chk1) Human CHEK1 and fission-yeast Chk1 are assigned to different PANTHER families (PTHR24346 and PTHR43895 respectively), so no family term is asserted; grounding is through the representative members.
Representative Members: CHEK1UniProtKB:O14757 chk1UniProtKB:P34208

Function

protein serine/threonine kinase activityGO:0004674
Targets: Cdc25 (inhibitory phosphorylation) Wee1/Mik1 (stabilising phosphorylation)

Processes

mitotic G2/M transition checkpointGO:0044818

Converts DNA-damage and replication-stress signals into inhibition of the CDK1 activation switch.

PMID:11298456
Checkpoint kinase phosphorylation of Cdc25A targets it for degradation.
PMID:10637286
Checkpoint signalling regulates Mik1 to enforce the G2/M DNA damage delay.