cdc25 (S. pombe) review notes

UniProt: P06652 (MPIP_SCHPO), gene SPAC24H6.05. "M-phase inducer phosphatase" / p80cdc25.
596 aa, Rhodanese-like catalytic domain (429-533), active-site phosphocysteine intermediate at Cys480.

Core function

cdc25 is the protein-tyrosine phosphatase that dephosphorylates Cdc2 (CDK1) on Tyr15, the rate-limiting
step triggering mitotic entry. It is the positive counterpart of the Wee1/Mik1 tyrosine kinases.

• PMID:3955656 — also notes it "functions to counteract the activity of the mitotic inhibitor wee1+".
• PMID:1756737. C-terminal 23 kDa is the active domain; GST-cdc25 dephosphorylates pNPP and phospho-casein; "Reaction requirements and inhibitor sensitivities were the same as those of phosphotyrosine phosphatases (PTPases)"; "Mutation of the cdc25 Cys480 codon ... abolished the phosphatase activity". → catalytic, active-site cysteine confirmed.
• PMID:1703321 — human PTPase complements p80cdc25.
• PMID:1819507 (note: "phosphate" is a typo for phosphatase in source). Level of p80cdc25 rises as cells approach mitosis; timing of mitosis sensitive to cdc25+ dosage.
• PMID:2665944.

EC 3.1.3.48 (protein-tyrosine-phosphatase). MF: protein tyrosine phosphatase activity (GO:0004725) — core, strongly supported.
GO:0004721 phosphoprotein phosphatase activity (IDA, PMID:22665807) is a broader parent; the IDA in that paper is about Cdk1/Clp1 phosphoregulation of Cdc25 — keep but the tyrosine-specific term is more informative.

Cell size control / positive regulation of G2/M

• PMID:28479325 and "smaller cells express less Cdc25 and larger cells express more Cdc25, creating an increasing concentration of Cdc25 as cells grow and providing a mechanism for cells to trigger cell division when they reach a threshold concentration of Cdc25." This is mitotic G2 cell size control checkpoint (GO:0031569, IMP). Cell-size regulation (GO:0008361, NAS) is the older keyword-based statement.
• PMID:22665807 — Cdk1-Cdc25 positive feedback; Clp1/Cdc14 reverses it at mitotic exit.

Checkpoint regulation (Cdc25 is the TARGET, inhibited by checkpoint kinases)

• PMID:9278510; "Cdc25 associated with Chk1 in vivo and was phosphorylated when copurified in Chk1 complexes." → response to mitotic G2 DNA damage checkpoint signaling (GO:0072435, IMP); protein binding with chk1 (SPCC1259.13).
• PMID:9774107; "Chk1 functions redundantly with the kinase Cds1 at the replication checkpoint and ... both kinases phosphorylate Cdc25 on the same sites, which include serine residues at positions 99, 192 and 359." IPI partners: cds1 (SPAC17A2.13c) and rad24 14-3-3 (SPAC8E11.02c).
• PMID:10523629; wild-type Cdc25 shuttles (nuclear accumulation with leptomycin B); Rad24 (14-3-3) overproduction → cytoplasmic. IPI partner rad24 (SPAC8E11.02c).
• PMID:9042863 — PomBase used this for PTP activity IMP.
• PMID:15297457 intra-S DNA damage checkpoint: Rad3-Cds1 pathway targets Cdc2; Cdc25 IMP for GO:0031573.
• PMID:15629716 Localization: cytoplasm + nucleus (IDA).
• PMID:18272791. IDA nucleus + cytosol.

Localization

• Cytoplasm + nucleus, shuttling; highest nuclear in G2. PMID:15629716, PMID:10523629, PMID:28479325.
• HDA cytosol (PMID:16823372 ORFeome global localization).
• PMID:1500423 is the MAMMALIAN cdc25 (nuclear), not S. pombe — annotated to P06652 by PomBase as orthologous support for nucleus. Keep but note it is heterologous evidence.

Meiosis (non-core, but genuine)

cdc25 is also required for meiotic nuclear divisions (meiosis I onset), via the same Cdc2-Tyr15 dephosphorylation, downstream of the meiotic transcription factor Mei4.
- PMID:17804800. Mei4 activates cdc25+ transcription. → GO:0110044 regulation of cell cycle switching, mitotic to meiotic (IMP) and GO:0110032 positive regulation of G2/MI transition of meiotic cell cycle.
- PMID:25492408; "Cdc25 triggers entry to nuclear divisions downstream of the replication checkpoint independently of Mei4." → GO:0110032 (IMP).

These meiotic roles are the SAME biochemical activity (Cdc2-Y15 dephosphorylation) deployed in the meiotic cell cycle; they are real (not SPKW keyword artifacts) but are not the single core function — keep as non-core.

Protein binding (IPI) — replace bare protein binding where possible

• PMID:9278510 with chk1 (SPCC1259.13): Cdc25 is a substrate/binding partner of the Chk1 checkpoint kinase. Could be modeled as kinase binding, but the experimental finding is being a checkpoint-kinase target.
• PMID:9774107 with cds1 (SPAC17A2.13c) AND rad24 14-3-3 (SPAC8E11.02c): substrate of Cds1; binds 14-3-3.
• PMID:10523629 with rad24 (SPAC8E11.02c): 14-3-3 binding.
• PMID:11812792 with suc1/p13suc1 (SPBC1734.14c): this NMR paper is about p13suc1/CKS; the cdc25 IPI here is weak/peripheral. The paper does not actually characterize a Cdc25-Suc1 interaction in detail — mark as over-annotated / undecided (paper is about suc1 structure, not cdc25).

GO curation guideline: avoid bare "protein binding" (GO:0005515). For the 14-3-3 interactions, GO:0071889 (14-3-3 protein binding) is the informative term. For chk1/cds1 (these kinases act ON cdc25), the relationship is best captured by the BP checkpoint terms rather than a generic MF; suggest MODIFY rad24 IPIs to 14-3-3 protein binding, and mark the others as over-annotated (uninformative protein binding).