Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: CDC25B shuttles between nucleus and cytoplasm. 14-3-3 binding sequesters it in the cytoplasm during interphase, but it translocates to the nucleus as part of its activation cycle. Multiple studies confirm nuclear localization. Reason: IBA annotation is well supported. CDC25B is known to shuttle between nucleus and cytoplasm, with nuclear localization being part of its functional cycle for activating CDK1-cyclin B complexes (PMID:15173315, PMID:12764136). UniProt subcellular location also describes centrosomal and spindle pole localization, both of which require transit through the nucleus/cytoplasm. Supporting Evidence: PMID:15173315 Binding of 14-3-3beta but not 14-3-3sigma controls the cytoplasmic localization of CDC25B PMID:12764136 14-3-3 acts as an intramolecular bridge to regulate cdc25B localization and activity
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: CDC25B is present in the cytoplasm, where it is sequestered by 14-3-3 proteins during interphase. It also functions at the centrosome, which is in the cytoplasm. Reason: IBA annotation is well supported. CDC25B localizes to cytoplasm during interphase via 14-3-3 binding and functions at the centrosome (a cytoplasmic structure) during the G2/M transition (PMID:15128871, PMID:15908796). Supporting Evidence: PMID:15173315 Binding of 14-3-3beta but not 14-3-3sigma controls the cytoplasmic localization of CDC25B
GO:0000086 G2/M transition of mitotic cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: CDC25B is a key regulator of the G2/M transition, functioning as a "starter phosphatase" that initiates activation of CDK1-cyclin B at the centrosome. Reason: This is one of the most well-established functions of CDC25B. The IBA annotation reflects the conserved core function across species. Multiple primary studies confirm CDC25B drives G2/M transition through dephosphorylation of CDK1 (PMID:20360007, PMID:1836978, PMID:17332740). Supporting Evidence: PMID:20360007 Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation of Cdk1-cyclin B complexes, whereas repression of these phosphatases by short hairpin RNA has a reverse effect PMID:1836978 cdc25A and cdc25B display endogenous tyrosine phosphatase activity that is stimulated several-fold, in the absence of cdc2, by stoichiometric addition of either cyclin B1 or B2
GO:0004725 protein tyrosine phosphatase activity	IBA GO_REF:0000033	ACCEPT	Summary: CDC25B is a dual-specificity phosphatase that removes phosphates from both phosphotyrosine and phosphothreonine residues on CDKs. The protein tyrosine phosphatase activity annotation captures the tyrosine phosphatase component. Reason: IBA annotation is correct. CDC25B dephosphorylates Tyr15 (and Thr14) on CDK1. The original characterization demonstrated endogenous tyrosine phosphatase activity (PMID:1836978). EC 3.1.3.48 classifies it as a protein-tyrosine-phosphatase. While CDC25B is technically a dual-specificity phosphatase, the protein tyrosine phosphatase activity term is appropriate since it does remove phosphotyrosine. Supporting Evidence: PMID:1836978 cdc25A and cdc25B display endogenous tyrosine phosphatase activity
GO:0010971 positive regulation of G2/M transition of mitotic cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: CDC25B positively regulates the G2/M transition by dephosphorylating and activating CDK1-cyclin B complexes. This is the core evolved function. Reason: This annotation accurately captures CDC25B's role as a positive regulator of mitotic entry. CDC25B dephosphorylation of CDK1 promotes G2/M transition (PMID:20360007, PMID:1836978). Supporting Evidence: PMID:20360007 Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation of Cdk1-cyclin B complexes
GO:0110032 positive regulation of G2/MI transition of meiotic cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: CDC25B has been implicated in meiotic cell cycle regulation. UniProt lists GO annotations for oocyte maturation and female meiosis I (IEA from Ensembl), consistent with a conserved role in meiotic G2/M transition. Reason: IBA annotations have undergone phylogenetic review and are generally at the right level of specificity. CDC25B is known to function in oocyte maturation and meiotic cell cycle entry in vertebrates, consistent with this annotation. UniProt lists IEA annotations for female meiosis I and oocyte maturation based on Ensembl data.
GO:0000922 spindle pole	IEA GO_REF:0000044	ACCEPT	Summary: CDC25B localizes to spindle poles during mitosis, as demonstrated by immunofluorescence with phospho-specific antibodies. Reason: This IEA annotation is confirmed by direct experimental evidence. UniProt explicitly lists spindle pole as a subcellular location based on PMID:15908796. The IDA annotation for the same term (below) provides the experimental backing. Supporting Evidence: PMID:15908796 CDC25B phosphorylated by pEg3 localizes to the centrosome and the spindle poles at mitosis
GO:0004721 phosphoprotein phosphatase activity	IEA GO_REF:0000043	ACCEPT	Summary: CDC25B has phosphoprotein phosphatase activity, dephosphorylating CDK1 at inhibitory Thr14 and Tyr15 residues. Reason: This IEA annotation from UniProt keyword mapping is correct. CDC25B is classified as EC 3.1.3.48, a protein-tyrosine-phosphatase, and its function is to dephosphorylate CDK1. This broader term encompasses the more specific protein tyrosine phosphatase activity also annotated. Supporting Evidence: PMID:20360007 dephosphorylation is catalyzed by the dual specific Cdc25 phosphatases
GO:0004725 protein tyrosine phosphatase activity	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate IEA annotation for protein tyrosine phosphatase activity from combined automated methods. Reason: Same term as the IBA annotation above; this IEA confirms via automated methods what is well established experimentally. CDC25B is classified as EC 3.1.3.48 and has demonstrated tyrosine phosphatase activity (PMID:1836978).
GO:0005813 centrosome	IEA GO_REF:0000044	ACCEPT	Summary: CDC25B localizes to the centrosome, where it initiates activation of CDK1-cyclin B at the G2/M transition. Reason: IEA annotation is well supported by experimental data. UniProt lists centrosome as a subcellular location with experimental evidence from PMID:15128871, PMID:15311285, and PMID:15908796. CDC25B functions as a "starter phosphatase" at the centrosome. Supporting Evidence: PMID:15908796 CDC25B phosphorylated by pEg3 localizes to the centrosome and the spindle poles at mitosis
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: CDC25B is a phosphatase (hydrolase) that cleaves phosphoester bonds on CDK substrates. Reason: This is a very broad parent term for the more specific phosphatase activities also annotated. While not very informative on its own, it is not incorrect as phosphatases are hydrolases. The IEA from keyword mapping is acceptable as a broader classification.
GO:0051301 cell division	IEA GO_REF:0000043	ACCEPT	Summary: CDC25B is involved in cell division through its role in activating CDK1-cyclin B for mitotic entry and its requirement for cytokinesis. Reason: This IEA from UniProt keyword mapping is correct. CDC25B promotes cell division through its role at G2/M transition and its requirement for abscission during cytokinesis (PMID:17332740). This broad term encompasses both functions. Supporting Evidence: PMID:17332740 PRK2 is required for abscission of the midbody at the end of the cell division cycle and for phosphorylation and activation of Cdc25B
GO:1902751 positive regulation of cell cycle G2/M phase transition	IEA GO_REF:0000002	ACCEPT	Summary: CDC25B positively regulates the G2/M phase transition by dephosphorylating CDK1. Reason: This IEA annotation from InterPro mapping is correct and consistent with the IBA and IDA annotations for GO:0010971 (positive regulation of G2/M transition of mitotic cell cycle). This is the core function of CDC25B.
GO:0005515 protein binding	IPI PMID:10713667 Specific interaction between 14-3-3 isoforms and the human C...	MODIFY	Summary: PMID:10713667 demonstrates specific interaction between 14-3-3 isoforms (particularly zeta and eta) and CDC25B. This is a functionally significant interaction regulating CDC25B localization and activity. Reason: The interaction with 14-3-3 proteins is well documented and functionally significant, but "protein binding" is too vague per curation guidelines. The interaction with 14-3-3 proteins should be annotated with a more specific term. CDC25B binds 14-3-3 via phosphoserine motifs, and this regulates its subcellular localization and activity. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:10713667 CDC25 dual-specificity phosphatases are essential regulators that activate cyclin-dependent kinases (CDKs) at critical stages of the cell cycle... a specific, strong interaction between CDC25B and 14-3-3zeta and eta isoforms is revealed by a deletion of 288 residues in the amino-terminal region of CDC25B
GO:0005515 protein binding	IPI PMID:12764136 14-3-3 acts as an intramolecular bridge to regulate cdc25B l...	MODIFY	Summary: PMID:12764136 shows 14-3-3 acts as an intramolecular bridge to regulate CDC25B localization and activity. This is a specific 14-3-3 binding interaction. Reason: Should use a more specific term than protein binding. This study demonstrates 14-3-3 binding to CDC25B. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:12764136 14-3-3 acts as an intramolecular bridge to regulate cdc25B localization and activity
GO:0005515 protein binding	IPI PMID:12766774 Dual phosphorylation controls Cdc25 phosphatases and mitotic...	MODIFY	Summary: PMID:12766774 describes dual phosphorylation controlling Cdc25 phosphatases and mitotic entry, likely involving checkpoint kinase-dependent 14-3-3 binding. Reason: Protein binding is too vague. The context from the title suggests phosphorylation- dependent interactions controlling CDC25 function, likely 14-3-3 binding. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:12766774 Dual phosphorylation controls Cdc25 phosphatases and mitotic entry
GO:0005515 protein binding	IPI PMID:12871587 Interaction of 14-3-3 with Bid during seizure-induced neuron...	UNDECIDED	Summary: PMID:12871587 is about interaction of 14-3-3 with Bid during seizure-induced neuronal death. The relevance to CDC25B is unclear from the abstract. Reason: This paper is primarily about 14-3-3 interaction with Bid in neuronal death contexts. It is not clear how this directly supports a CDC25B protein binding annotation. Unable to verify relevance without full text access. Supporting Evidence: PMID:12871587 Interaction of 14-3-3 with Bid during seizure-induced neuronal death
GO:0005515 protein binding	IPI PMID:15173315 Binding of 14-3-3beta but not 14-3-3sigma controls the cytop...	MODIFY	Summary: PMID:15173315 demonstrates 14-3-3beta binding to CDC25B controls cytoplasmic localization. This is a specific and functionally relevant interaction. Reason: Should use a more specific term. This study specifically examines 14-3-3 binding to CDC25B and its effects on subcellular localization. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:15173315 Binding of 14-3-3beta but not 14-3-3sigma controls the cytoplasmic localization of CDC25B
GO:0005515 protein binding	IPI PMID:15629715 MAPKAP kinase-2 is a cell cycle checkpoint kinase that regul...	MODIFY	Summary: PMID:15629715 shows MAPKAPK2 phosphorylates CDC25B at Ser323, creating a 14-3-3 binding site. The interaction demonstrated is between CDC25B and its upstream kinase MAPKAPK2 and downstream binding partner 14-3-3. Reason: Protein binding is too vague. The CDC25B interaction described involves both kinase binding (MAPKAPK2) and 14-3-3 binding. The 14-3-3 binding is the more specific annotation. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:15629715 MAPKAP kinase-2 is directly responsible for Cdc25B/C phosphorylation and 14-3-3 binding in vitro and in response to UV-induced DNA damage within mammalian cells
GO:0005515 protein binding	IPI PMID:16672277 Amino acids C-terminal to the 14-3-3 binding motif in CDC25B...	MODIFY	Summary: PMID:16672277 examines amino acids C-terminal to the 14-3-3 binding motif in CDC25B that affect 14-3-3 binding efficiency. Specific 14-3-3 interaction study. Reason: This is specifically about 14-3-3 binding to CDC25B and should be annotated with the more specific term. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:16672277 Amino acids C-terminal to the 14-3-3 binding motif in CDC25B affect the efficiency of 14-3-3 binding
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	MARK AS OVER ANNOTATED	Summary: PMID:26496610 is a large-scale interactome study. Protein binding from high-throughput studies is generally uninformative without specific partner context. Reason: High-throughput interactome study. Protein binding annotations from such studies do not provide specific functional information about CDC25B interactions. Supporting Evidence: PMID:26496610 A human interactome in three quantitative dimensions organized by stoichiometries and abundances
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: PMID:28514442 is a large-scale interactome mapping study. Reason: High-throughput interactome study providing uninformative protein binding annotation. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: PMID:32296183 is a large-scale binary interactome mapping study. Reason: High-throughput interactome study. Generic protein binding annotation is not informative for functional annotation. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: PMID:33961781 is a large-scale proteome-scale interactome study. Reason: High-throughput interactome study. Generic protein binding is uninformative. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: PMID:35271311 (OpenCell) is a large-scale endogenous tagging and interactome study. Reason: High-throughput study. Generic protein binding is not informative for CDC25B functional annotation. Supporting Evidence: PMID:35271311 Endogenous tagging for the cartography of human cellular organization
GO:0005515 protein binding	IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c...	MODIFY	Summary: PMID:36931259 describes a chaperone-like role for 14-3-3 proteins. The interaction with CDC25B is a known 14-3-3 client interaction. Reason: Should use the more specific 14-3-3 protein binding term. CDC25B is a well-known 14-3-3 client protein. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human cells
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: PMID:40205054 is a large-scale multimodal cell map study. Reason: High-throughput study. Generic protein binding is not informative. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics
GO:0005515 protein binding	IPI PMID:7644510 14-3-3 proteins associate with cdc25 phosphatases.	MODIFY	Summary: PMID:7644510 is one of the original studies demonstrating 14-3-3 association with cdc25 phosphatases via yeast two-hybrid screen. This is a functionally significant interaction. Reason: Should use the more specific 14-3-3 protein binding term. This foundational paper identified 14-3-3 epsilon and beta as CDC25B-interacting proteins. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:7644510 Two members of the 14-3-3 protein family have been isolated in a yeast two-hybrid screen designed to identify proteins that interact with the human cdc25A and cdc25B phosphatases
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for nuclear localization, consistent with the IBA annotation above. Reason: Consistent with the IBA annotation and known biology of CDC25B nuclear-cytoplasmic shuttling.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for cytoplasmic localization, consistent with the IBA annotation above. Reason: Consistent with the IBA annotation and known cytoplasmic localization of CDC25B during interphase via 14-3-3 sequestration.
GO:0000086 G2/M transition of mitotic cell cycle	TAS Reactome:R-HSA-69275	ACCEPT	Summary: TAS annotation from Reactome G2/M Transition pathway. CDC25B is a central component of this pathway. Reason: Reactome correctly includes CDC25B in the G2/M transition pathway. This is the core biological process for CDC25B.
GO:0004721 phosphoprotein phosphatase activity	TAS Reactome:R-HSA-170153	ACCEPT	Summary: TAS from Reactome pathway for dephosphorylation of nuclear Cyclin B1:phospho-Cdc2 complexes by Cdc25 phosphatases. Reason: Correctly annotates CDC25B's phosphoprotein phosphatase activity in the context of dephosphorylating CDK1-cyclin B complexes in the nucleus.
GO:0004721 phosphoprotein phosphatase activity	TAS Reactome:R-HSA-170161	ACCEPT	Summary: TAS from Reactome pathway for dephosphorylation of cytoplasmic Cyclin B1/B2: phospho-Cdc2 complexes specifically by CDC25B. Reason: Correctly annotates CDC25B's phosphoprotein phosphatase activity. Reactome R-HSA-170161 specifically names CDC25B as the phosphatase for cytoplasmic CDK1-cyclin B dephosphorylation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9929935	ACCEPT	Summary: TAS from Reactome pathway CCNA:CDK1 phosphorylates CDC25B, placing CDC25B in the nucleoplasm. Reason: CDC25B is phosphorylated by Cyclin A:CDK1 complexes in the nucleus, consistent with nucleoplasmic localization during parts of its functional cycle.
GO:0004721 phosphoprotein phosphatase activity	IDA PMID:20360007 Cdc25 phosphatases are required for timely assembly of CDK1-...	ACCEPT	Summary: PMID:20360007 directly demonstrates that CDC25B has phosphoprotein phosphatase activity, dephosphorylating CDK1 to promote assembly and activation of CDK1-cyclin B complexes at G2/M. Reason: Direct experimental demonstration (IDA) of CDC25B phosphatase activity. The study shows overexpression of CDC25B promotes CDK1-cyclin B assembly and activation while knockdown inhibits it (PMID:20360007). Supporting Evidence: PMID:20360007 Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation of Cdk1-cyclin B complexes, whereas repression of these phosphatases by short hairpin RNA has a reverse effect, leading to a substantial decrease in amounts of cyclin B-bound Cdk1 in G(2) and mitosis
GO:0010971 positive regulation of G2/M transition of mitotic cell cycle	IDA PMID:20360007 Cdc25 phosphatases are required for timely assembly of CDK1-...	ACCEPT	Summary: PMID:20360007 directly demonstrates CDC25B positively regulates G2/M transition through effects on CDK1-cyclin B complex assembly and activation. Reason: Direct experimental evidence (IDA) confirming CDC25B's role as a positive regulator of G2/M transition. Overexpression accelerates G2/M while knockdown delays it (PMID:20360007). Supporting Evidence: PMID:20360007 Cdc25A and Cdc25B, but not Cdc25C phosphatases have an effect on timing and efficiency of cyclin-kinase complex formation
GO:0005829 cytosol	TAS Reactome:R-HSA-8863007	ACCEPT	Summary: TAS from Reactome pathway for p25-bound CDK5 phosphorylation of CDC25B, placing CDC25B in the cytosol. Reason: CDC25B is present in the cytosol as part of its nucleocytoplasmic shuttling and centrosomal localization cycle. Reactome places it in the cytosol for CDK5-mediated phosphorylation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-170120	ACCEPT	Summary: TAS from Reactome for translocation of Cdc25B to the cytoplasm, implying nucleoplasmic origin. Reason: CDC25B translocates from nucleus to cytoplasm, consistent with nucleoplasmic localization before translocation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-170153	ACCEPT	Summary: TAS from Reactome for dephosphorylation of nuclear Cyclin B1:phospho-Cdc2 complexes, placing CDC25B in nucleoplasm. Reason: CDC25B dephosphorylates CDK1-cyclin B complexes in the nucleus, consistent with nucleoplasmic localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-170159	ACCEPT	Summary: TAS from Reactome for translocation of Cdc25 to the nucleus. Reason: CDC25B translocates to the nucleus as part of its activation cycle.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9926524	ACCEPT	Summary: TAS from Reactome for MITF-M-dependent CDC25B gene expression, placing CDC25B in the nucleoplasm. Reason: Consistent with nucleoplasmic localization of CDC25B.
GO:0005829 cytosol	TAS Reactome:R-HSA-170120	ACCEPT	Summary: TAS from Reactome for translocation of Cdc25B to the cytoplasm. Reason: CDC25B translocates to the cytoplasm/cytosol during its regulation cycle, where it is sequestered by 14-3-3 proteins.
GO:0005829 cytosol	TAS Reactome:R-HSA-170159	ACCEPT	Summary: TAS from Reactome for translocation of Cdc25 to the nucleus, implying cytosolic origin before translocation. Reason: CDC25B is in the cytosol before translocating to the nucleus.
GO:0005829 cytosol	TAS Reactome:R-HSA-170161	ACCEPT	Summary: TAS from Reactome for dephosphorylation of cytoplasmic Cyclin B1/B2: phospho-Cdc2 complexes by CDC25B. Reason: CDC25B dephosphorylates CDK1-cyclin B complexes in the cytosol, consistent with its centrosomal activation function.
GO:0006468 protein phosphorylation	IDA PMID:17332740 Rho GTPases regulate PRK2/PKN2 to control entry into mitosis...	REMOVE	Summary: CRITICAL MISANNOTATION: CDC25B is a PHOSPHATASE (EC 3.1.3.48), NOT a kinase. UniProt states it "Directly dephosphorylates CDK1 and stimulates its kinase activity." PMID:17332740 describes CDC25B as "the phosphatase required for activation of mitotic cyclin/Cdk1 complexes" - it dephosphorylates CDK1 to activate it. Annotating a phosphatase to "protein phosphorylation" is incorrect. Reason: CDC25B is a phosphatase that removes phosphate groups from CDK1. The paper PMID:17332740 describes PRK2/PKN2 as the kinase that phosphorylates CDC25B, and CDC25B as the phosphatase downstream. The annotation of CDC25B to "protein phosphorylation" (GO:0006468) confuses the fact that CDC25B is a substrate of phosphorylation with CDC25B performing phosphorylation. CDC25B performs dephosphorylation, not phosphorylation. Supporting Evidence: PMID:17332740 PRK2 is required for abscission of the midbody at the end of the cell division cycle and for phosphorylation and activation of Cdc25B, the phosphatase required for activation of mitotic cyclin/Cdk1 complexes at the G2/M transition
GO:0032467 positive regulation of cytokinesis	IMP PMID:17332740 Rho GTPases regulate PRK2/PKN2 to control entry into mitosis...	KEEP AS NON CORE	Summary: PMID:17332740 demonstrates that CDC25B is required for abscission during cytokinesis in an ECT2-dependent manner, supporting a role in positive regulation of cytokinesis. Reason: While the core function of CDC25B is G2/M transition regulation, the role in cytokinesis is a secondary function demonstrated by IMP evidence. The paper shows PRK2 controls exit from cytokinesis through CDC25B and ECT2 (PMID:17332740). UniProt also notes CDC25B is "Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner." This is a real but non-core function. Supporting Evidence: PMID:17332740 PRK2 is required for abscission of the midbody at the end of the cell division cycle and for phosphorylation and activation of Cdc25B
GO:0045931 positive regulation of mitotic cell cycle	IMP PMID:17332740 Rho GTPases regulate PRK2/PKN2 to control entry into mitosis...	ACCEPT	Summary: PMID:17332740 shows CDC25B positively regulates mitotic cell cycle entry via PRK2-dependent phosphorylation and activation. Reason: This annotation is correct. CDC25B promotes entry into mitosis by activating CDK1-cyclin B complexes. The paper demonstrates PRK2 phosphorylates and activates CDC25B for mitotic entry (PMID:17332740). This is consistent with the core function of CDC25B. Supporting Evidence: PMID:17332740 PRK2 is required for abscission of the midbody at the end of the cell division cycle and for phosphorylation and activation of Cdc25B, the phosphatase required for activation of mitotic cyclin/Cdk1 complexes at the G2/M transition
GO:0000086 G2/M transition of mitotic cell cycle	TAS PMID:12400006 Human pEg3 kinase associates with and phosphorylates CDC25B ...	ACCEPT	Summary: PMID:12400006 describes pEg3 kinase associating with and phosphorylating CDC25B, with implications for G2/M cell cycle regulation. Reason: CDC25B's role in G2/M transition is well established. This paper provides additional evidence by showing pEg3 kinase regulates CDC25B at the G2/M boundary (PMID:12400006). Supporting Evidence: PMID:12400006 CDC25B is one of the three CDC25 phosphatase genes identified in human. It is thought to regulate the G2/M progression by dephosphorylating and activating the CDK/cyclin complexes
GO:0000922 spindle pole	IDA PMID:15908796 CDC25B phosphorylated by pEg3 localizes to the centrosome an...	ACCEPT	Summary: PMID:15908796 demonstrates by immunofluorescence with phospho-specific antibodies that CDC25B phosphorylated at Ser169 by pEg3 localizes to spindle poles during mitosis. Reason: Direct experimental evidence (IDA) for spindle pole localization. The study uses phosphoepitope-specific antibodies to show the phosphorylated form of CDC25B at spindle poles during mitosis (PMID:15908796). UniProt also lists spindle pole as a confirmed subcellular location. Supporting Evidence: PMID:15908796 using phosphoepitope-specific antibodies we show that serine 169 is phosphorylated in vivo, that this phosphorylated form of CDC25B accumulates during mitosis, and is localized to the centrosomes
GO:0005813 centrosome	IDA PMID:15908796 CDC25B phosphorylated by pEg3 localizes to the centrosome an...	ACCEPT	Summary: PMID:15908796 directly demonstrates CDC25B localization to the centrosome during mitosis, confirmed by phospho-specific antibodies for Ser169. Reason: Direct experimental evidence (IDA) for centrosomal localization. CDC25B functions as a "starter phosphatase" at the centrosome, and this is one of the key localization sites for its G2/M function. UniProt confirms centrosome as a subcellular location with multiple supporting references. Supporting Evidence: PMID:15908796 CDC25B phosphorylated by pEg3 localizes to the centrosome and the spindle poles at mitosis
GO:0019901 protein kinase binding	IPI PMID:12400006 Human pEg3 kinase associates with and phosphorylates CDC25B ...	ACCEPT	Summary: PMID:12400006 demonstrates that pEg3 (MELK) kinase physically associates with CDC25B in vitro and in vivo, and phosphorylates CDC25B at Ser323. Reason: CDC25B binds multiple protein kinases including pEg3/MELK (PMID:12400006), AURKA (PMID:15128871), CHEK1 (PMID:15311285), and MAPKAPK2 (PMID:15629715). These are functionally significant interactions as CDC25B is a substrate of these kinases. Protein kinase binding is an appropriate term. Supporting Evidence: PMID:12400006 pEg3 is also able to specifically associate with CDC25B in vitro and in vivo
GO:0019901 protein kinase binding	IPI PMID:15908796 CDC25B phosphorylated by pEg3 localizes to the centrosome an...	ACCEPT	Summary: PMID:15908796 confirms pEg3 kinase interaction with CDC25B, showing phosphorylation-dependent localization effects. Reason: Confirms protein kinase binding between pEg3/MELK and CDC25B. The study shows pEg3 phosphorylates CDC25B at Ser169 and this interaction controls centrosomal localization (PMID:15908796). Supporting Evidence: PMID:15908796 we study the phosphorylation of CDC25B at mitosis by the kinase pEg3, a member of the KIN1/PAR-1/MARK family
GO:0000278 mitotic cell cycle	TAS PMID:1836978 Specific activation of cdc25 tyrosine phosphatases by B-type...	ACCEPT	Summary: PMID:1836978 is the original characterization of CDC25B showing it has tyrosine phosphatase activity activated by B-type cyclins and is involved in the mitotic cell cycle. Reason: Foundational paper establishing CDC25B as a mitotic cell cycle regulator. The study shows CDC25B is activated by cyclin B1/B2 and functions in mitotic regulation (PMID:1836978). Supporting Evidence: PMID:1836978 cdc25A and cdc25B display endogenous tyrosine phosphatase activity that is stimulated several-fold, in the absence of cdc2, by stoichiometric addition of either cyclin B1 or B2 but not A or D1
GO:0004725 protein tyrosine phosphatase activity	TAS PMID:1836978 Specific activation of cdc25 tyrosine phosphatases by B-type...	ACCEPT	Summary: PMID:1836978 demonstrates endogenous tyrosine phosphatase activity of CDC25B that is stimulated by B-type cyclins. Reason: The original study demonstrating CDC25B has tyrosine phosphatase activity. This is the core enzymatic activity of CDC25B (PMID:1836978). Supporting Evidence: PMID:1836978 cdc25A and cdc25B display endogenous tyrosine phosphatase activity
GO:0008284 positive regulation of cell population proliferation	TAS PMID:8276402 Chromosome mapping of human CDC25A and CDC25B phosphatases.	MARK AS OVER ANNOTATED	Summary: PMID:8276402 maps CDC25A and CDC25B chromosomal locations and discusses their potential as oncogenes due to their role in promoting cell division. No direct experimental evidence for cell proliferation regulation is provided. Reason: PMID:8276402 is a chromosome mapping study that only mentions the potential role of CDC25B as an oncogene based on its function in cell division. It does not directly demonstrate positive regulation of cell population proliferation. While CDC25B overexpression is associated with cancer, this is a pleiotropic effect rather than a core functional annotation. Supporting Evidence: PMID:8276402 the genes encoding these phosphatases may be suspected as potential oncogenes due to their role in promoting cell division
GO:0000278 mitotic cell cycle	TAS PMID:9188863 Alternative splicing of the human CDC25B tyrosine phosphatas...	ACCEPT	Summary: PMID:9188863 identifies alternative splice variants of CDC25B and shows their cell cycle regulation in G2 phase. Reason: The study confirms CDC25B expression is cell cycle regulated, peaking in G2, and that the variants function as mitotic inducers (PMID:9188863). Supporting Evidence: PMID:9188863 In primary fibroblasts and in HeLa cells the CDC25B expression is cell cycle regulated, reaching a maximum in G2-phase
GO:0004725 protein tyrosine phosphatase activity	TAS PMID:9188863 Alternative splicing of the human CDC25B tyrosine phosphatas...	ACCEPT	Summary: PMID:9188863 confirms CDC25B splice variants have tyrosine phosphatase activity with different levels of activity. Reason: The study demonstrates all three CDC25B splice variants have phosphatase activity (PMID:9188863), confirming the protein tyrosine phosphatase annotation. Supporting Evidence: PMID:9188863 In vitro, CDC25B1 phosphatase is slightly more active than CDC25B2 and B3

Core Functions

Dual-specificity phosphatase that dephosphorylates CDK1 (at inhibitory Thr14 and Tyr15) to activate CDK1-cyclin B complexes at the G2/M transition of the mitotic cell cycle

Molecular Function:

protein tyrosine phosphatase activity

Directly Involved In:

positive regulation of G2/M transition of mitotic cell cycle

Cellular Locations:

centrosome

Supporting Evidence:

PMID:20360007
Cdc25A and Cdc25B, but not Cdc25C phosphatases have an effect on timing and efficiency of cyclin-kinase complex formation
PMID:1836978
cdc25A and cdc25B display endogenous tyrosine phosphatase activity that is stimulated several-fold, in the absence of cdc2, by stoichiometric addition of either cyclin B1 or B2

14-3-3 binding regulates CDC25B nucleocytoplasmic shuttling. Phosphorylation at Ser323 and Ser375 creates 14-3-3 binding sites that sequester CDC25B in the cytoplasm during interphase and in response to DNA damage checkpoint activation.

Molecular Function:

14-3-3 protein binding

Directly Involved In:

G2/M transition of mitotic cell cycle

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:10713667
a specific, strong interaction between CDC25B and 14-3-3zeta and eta isoforms is revealed by a deletion of 288 residues in the amino-terminal region of CDC25B
PMID:15629715
MAPKAP kinase-2 is directly responsible for Cdc25B/C phosphorylation and 14-3-3 binding in vitro and in response to UV-induced DNA damage within mammalian cells

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10713667

Specific interaction between 14-3-3 isoforms and the human CDC25B phosphatase.

CDC25B interacts specifically with 14-3-3 zeta and eta isoforms through a high-affinity binding site requiring Ser323 integrity.

PMID:12400006

Human pEg3 kinase associates with and phosphorylates CDC25B phosphatase: a potential role for pEg3 in cell cycle regulation.

pEg3/MELK kinase phosphorylates CDC25B at Ser323 and physically associates with it in vitro and in vivo, regulating G2/M progression.

PMID:12764136

14-3-3 acts as an intramolecular bridge to regulate cdc25B localization and activity.

14-3-3 binding to CDC25B acts as an intramolecular bridge controlling localization and activity.

PMID:12766774

Dual phosphorylation controls Cdc25 phosphatases and mitotic entry.

Dual phosphorylation controls CDC25 phosphatase localization and mitotic entry through 14-3-3 binding.

PMID:12871587

Interaction of 14-3-3 with Bid during seizure-induced neuronal death.

PMID:15173315

Binding of 14-3-3beta but not 14-3-3sigma controls the cytoplasmic localization of CDC25B: binding site preferences of 14-3-3 subtypes and the subcellular localization of CDC25B.

14-3-3beta binding controls cytoplasmic localization of CDC25B while 14-3-3sigma does not.

PMID:15629715

MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation.

MAPKAPK2 phosphorylates CDC25B/C creating 14-3-3 binding sites as part of the DNA damage checkpoint response.

PMID:15908796

CDC25B phosphorylated by pEg3 localizes to the centrosome and the spindle poles at mitosis.

pEg3/MELK phosphorylates CDC25B at Ser169 and the phosphorylated form localizes to centrosomes and spindle poles during mitosis.

PMID:16672277

Amino acids C-terminal to the 14-3-3 binding motif in CDC25B affect the efficiency of 14-3-3 binding.

Residues C-terminal to the 14-3-3 binding motif in CDC25B modulate 14-3-3 binding efficiency.

PMID:17332740

Rho GTPases regulate PRK2/PKN2 to control entry into mitosis and exit from cytokinesis.

PRK2/PKN2 phosphorylates and activates CDC25B for mitotic entry and CDC25B is required for abscission during cytokinesis in an ECT2-dependent manner.

PMID:1836978

Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins.

CDC25B has endogenous tyrosine phosphatase activity stimulated by cyclin B1/B2 and was originally identified as a mitotic regulator.

PMID:20360007

Cdc25 phosphatases are required for timely assembly of CDK1-cyclin B at the G2/M transition.

CDC25A and CDC25B promote timely assembly and activation of CDK1-cyclin B complexes at G2/M. Knockdown delays complex formation.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:36931259

A central chaperone-like role for 14-3-3 proteins in human cells.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:7644510

14-3-3 proteins associate with cdc25 phosphatases.

14-3-3 epsilon and beta proteins were identified as CDC25A/B interacting partners by yeast two-hybrid screen.

PMID:8276402

Chromosome mapping of human CDC25A and CDC25B phosphatases.

CDC25B maps to chromosome 20p13. The paper discusses potential oncogenic role but provides no direct proliferation evidence.

PMID:9188863

Alternative splicing of the human CDC25B tyrosine phosphatase. Possible implications for growth control?

Three CDC25B splice variants (B1, B2, B3) identified with different phosphatase activities. Expression peaks in G2 phase.

Reactome:R-HSA-170120

Translocation of Cdc25B to the cytoplasm

Reactome:R-HSA-170153

Dephosphorylation of nuclear Cyclin B1:phospho-Cdc2 (Thr 14, Tyr15) complexes by Cdc25 phosphatases

Reactome:R-HSA-170159

Translocation of Cdc25 to the nucleus

Reactome:R-HSA-170161

Dephosphorylation of cytoplasmic Cyclin B1/B2:phospho-Cdc2 (Thr 14, Tyr 15) complexes by CDC25B

Reactome:R-HSA-69275

G2/M Transition

Reactome:R-HSA-8863007

p25-bound CDK5 phosphorylates CDC25B

Reactome:R-HSA-9926524

MITF-M-dependent CDC25B gene expression

Reactome:R-HSA-9929935

CCNA:CDK1 phosphorylates CDC25B

📚 Additional Documentation

Deep Research Falcon

(CDC25B-deep-research-falcon.md)

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organism_full: Homo sapiens (Human).
protein_family: Belongs to the MPI phosphatase family. .
protein_domains: MPI_Phosphatase. (IPR000751); Rhodanese-like_dom. (IPR001763);
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P30305
Protein Description: RecName: Full=M-phase inducer phosphatase 2; EC=3.1.3.48 {ECO:0000305|PubMed:20360007}; AltName: Full=Dual specificity phosphatase Cdc25B;
Gene Information: Name=CDC25B; Synonyms=CDC25HU2;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the MPI phosphatase family. .
Key Domains: MPI_Phosphatase. (IPR000751); Rhodanese-like_dom. (IPR001763); Rhodanese-like_dom_sf. (IPR036873); M-inducer_phosp (PF06617); Rhodanese (PF00581)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CDC25B" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CDC25B' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene CDC25B (gene ID: CDC25B, UniProt: P30305) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P30305
Protein Description: RecName: Full=M-phase inducer phosphatase 2; EC=3.1.3.48 {ECO:0000305|PubMed:20360007}; AltName: Full=Dual specificity phosphatase Cdc25B;
Gene Information: Name=CDC25B; Synonyms=CDC25HU2;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the MPI phosphatase family. .
Key Domains: MPI_Phosphatase. (IPR000751); Rhodanese-like_dom. (IPR001763); Rhodanese-like_dom_sf. (IPR036873); M-inducer_phosp (PF06617); Rhodanese (PF00581)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CDC25B" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene CDC25B (gene ID: CDC25B, UniProt: P30305) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research Report: Human CDC25B (UniProt P30305) — Functional Annotation and Translational Relevance

0) Target verification (required)

The UniProt accession P30305 corresponds to human CDC25B (“M-phase inducer phosphatase 2”; dual-specificity phosphatase; EC 3.1.3.48). Evidence reviewed here consistently refers to CDC25B/Cdc25B as a CDC25-family dual-specificity phosphatase (DSP) that activates cyclin-dependent kinases by removing inhibitory phosphates, with a conserved HCX5R active-site motif and catalytic Cys473 (abdelwahab2022acomprehensiveoverview pages 1-2, abdelwahab2022acomprehensiveoverview pages 2-4, davidson2023investigationofpin1 pages 30-34).

Topic	Key Details & Evidence
Identity & Domains	Name: CDC25B (M-phase inducer phosphatase 2); Family: MPI phosphatase / Dual Specificity Phosphatase (DSP). Structure: Conserved C-terminal catalytic domain with HCX5R motif (HCEFSSER); divergent N-terminal regulatory domain. Active Site: Shallow/flat pocket lacking a defined substrate groove; specificity relies on distal "hotspot" residues (e.g., R488, R492, Y497) 20–30 Å away (davidson2023investigationofpin1a pages 30-34, abdelwahab2022acomprehensiveoverview pages 1-2, davidson2023investigationofpin1 pages 30-34, davidson2023investigationofpin1a pages 34-37).
Enzymatic Reaction	Function: Removes inhibitory phosphates from Thr14 and Tyr15 of Cyclin-Dependent Kinases (CDKs). Substrate Specificity: Primary substrate is CDK1/Cyclin B; can also act on CDK2/Cyclin A/E. (davidson2023investigationofpin1a pages 30-34, abdelwahab2022acomprehensiveoverview pages 2-4, liu2020theroleof pages 2-3).
Catalytic Mechanism	Two-step Mechanism: 1. Nucleophilic attack by thiolate of Cys473 forms a covalent phospho-cysteine intermediate. 2. Hydrolysis of the intermediate by water, assisted by a catalytic aspartate. Key Residues: Cys473 (catalytic nucleophile), Arg479 (phosphate coordination). (abdelwahab2022acomprehensiveoverview pages 1-2, abdelwahab2022acomprehensiveoverview pages 2-4, davidson2023investigationofpin1 pages 30-34, zhang2018dualspecificityphosphatasecdc25b pages 1-2).
Cell Cycle Role	"Starter" Phosphatase: Initiates mitosis by activating CDK1/Cyclin B at the centrosome during the G2/M transition. Timing: Accumulates in late S/early G2; activity peaks at G2/M. (davidson2023investigationofpin1a pages 30-34, abdelwahab2022acomprehensiveoverview pages 1-2, canovas2024survivinmediatesmitotic pages 28-31, contourgalcera2007whatsnewon pages 1-2).
Regulation	Positive Feedback: CDK1/Cyclin B phosphorylates CDC25B to enhance activity. 14-3-3 Binding: Phosphorylated CDC25B (e.g., Ser323/Ser151) is bound by 14-3-3, sequestering it in the cytoplasm during interphase; release allows nuclear entry. Redox Switch: Highly sensitive to oxidation; forms a reversible intramolecular disulfide bond between catalytic Cys473 and "backdoor" Cys426, inactivating the enzyme (reversible by thioredoxin). (abdelwahab2022acomprehensiveoverview pages 2-4, davidson2023investigationofpin1a pages 34-37, he2023ser149isanother pages 1-6).
Localization	Shuttling: Shuttles between nucleus and cytoplasm. G2/M: Translocates to the cytoplasm/centrosome in late G2 to activate initial CDK1 pools; Survivin may bridge CDC25B-CDK1 interaction at centrosomes. (davidson2023investigationofpin1a pages 30-34, canovas2024survivinmediatesmitotic pages 28-31, contourgalcera2007whatsnewon pages 1-2).
Disease Relevance	Overexpression: Found in 78% of gastric cancers, 47% of gliomas, 57% of breast cancers, 43–67% of colorectal cancers. Correlates with poor prognosis. Neurodevelopment: Regulates neurogenic decisions/progenitor cell cycle length. (abdelwahab2022acomprehensiveoverview pages 2-4, contourgalcera2007whatsnewon pages 1-2, bona2020menadionereducescdc25b pages 6-8).
Therapeutic Targeting	Menadione (Vitamin K3): Inhibits CDC25B (Ki ~95 µM); reduces tumor growth in gastric cancer (in vivo). HB-21: Natural product; covalently binds Cys473 (IC50 = 24.25 µM). Other Inhibitors: IRC-083864 (low nM activity); NSC-95397 (IC50 ~10-18 µM in colon cancer); Adociaquinone B (IC50 ~0.07 µM). Challenges: Quinones often generate ROS or lack specificity; shallow active site makes rational design difficult. (zhang2018dualspecificityphosphatasecdc25b pages 1-2, abdelwahab2022acomprehensiveoverview pages 2-4, dakilah2024potentialofcdc25 pages 8-9, abdelwahab2022acomprehensiveoverview pages 8-10, bona2020menadionereducescdc25b pages 6-8).

Table: This table consolidates key findings regarding CDC25B's molecular identity, enzymatic mechanism, regulatory pathways, and role in disease, serving as a structured reference for the report.

1) Key concepts and definitions (current understanding)

1.1 CDC25B is a dual-specificity phosphatase (DSP) that activates CDKs

CDC25 phosphatases are “dual-specificity” in that they can dephosphorylate phosphoserine/threonine and phosphotyrosine residues; functionally their defining substrates are CDKs at the inhibitory sites Thr14 and Tyr15 (abdelwahab2022acomprehensiveoverview pages 1-2, liu2020theroleof pages 2-3). CDC25B is widely described as promoting the G2/M transition by activating CDK1–cyclin B through dephosphorylation of these inhibitory phosphosites (davidson2023investigationofpin1a pages 30-34, abdelwahab2022acomprehensiveoverview pages 2-4, liu2020theroleof pages 2-3).

1.2 Catalytic architecture: HCX5R motif and a cysteine-based PTP-like mechanism

Mechanistic and structural descriptions converge on a cysteine-based phosphatase mechanism analogous to classical protein tyrosine phosphatases (PTPs):
- The conserved HCX5R motif forms the catalytic loop, and the catalytic cysteine exists as a reactive thiolate that performs nucleophilic attack on the substrate phosphate (abdelwahab2022acomprehensiveoverview pages 1-2, davidson2023investigationofpin1 pages 30-34).
- Catalysis proceeds via a covalent phospho-cysteine intermediate, followed by hydrolysis to regenerate the enzyme (abdelwahab2022acomprehensiveoverview pages 1-2, abdelwahab2022acomprehensiveoverview pages 2-4, davidson2023investigationofpin1 pages 30-34).
For human CDC25B specifically, Cys473 is repeatedly identified as the catalytically essential cysteine (abdelwahab2022acomprehensiveoverview pages 1-2, abdelwahab2022acomprehensiveoverview pages 2-4, zhang2018dualspecificityphosphatasecdc25b pages 1-2).

1.3 Substrate recognition: shallow active site and distal “hotspot” residues

CDC25 catalytic pockets are described as flat/shallow and lacking a strong, peptide-like binding groove; therefore substrate specificity depends on features beyond the immediate catalytic pocket (davidson2023investigationofpin1a pages 30-34, davidson2023investigationofpin1 pages 30-34, liu2020theroleof pages 2-3). For CDC25B, distal hotspot residues (e.g., R488, R492, Y497) located ~20–30 Å from the active site have been described as contributing to recognition (davidson2023investigationofpin1a pages 30-34, davidson2023investigationofpin1 pages 30-34).

2) Molecular function and pathway role

2.1 Primary biochemical function: dephosphorylation of inhibitory CDK sites

A central, conserved functional statement is that CDC25B activates CDKs by removing inhibitory phosphates at Thr14 and Tyr15, thereby promoting mitotic entry via CDK1–cyclin B activation (davidson2023investigationofpin1a pages 30-34, abdelwahab2022acomprehensiveoverview pages 2-4, liu2020theroleof pages 2-3). Structural/docking discussions in the inhibitor literature describe interactions consistent with recognition of phosphorylated CDK activation-loop residues, including contacts of the phosphate with arginine in the CX5R motif (abdelwahab2022acomprehensiveoverview pages 2-4).

2.2 Cell-cycle systems role: “starter phosphatase” at the centrosome

CDC25B is frequently described as acting as a “starter” phosphatase that initiates activation of CDK1–cyclin B at the centrosome, helping trigger the G2/M transition (abdelwahab2022acomprehensiveoverview pages 1-2, contourgalcera2007whatsnewon pages 1-2). A recent mechanistic preprint (HeLa cells) further frames CDC25B as the phosphatase “first” activating centrosomal Cdk1, with survivin proposed to enable proper signaling through a CDC25B–Cdk1 axis (canovas2024survivinmediatesmitotic pages 28-31).

3) Regulation and subcellular localization

3.1 Phosphorylation-dependent 14-3-3 binding and nucleocytoplasmic shuttling

CDC25-family phosphatases are extensively regulated by phosphorylation and binding partners, including 14-3-3 proteins that sequester phosphatases and influence localization (davidson2023investigationofpin1a pages 34-37, contourgalcera2007whatsnewon pages 1-2). A 2023 preprint in mouse embryos identifies a phosphorylation site (Ser149 in mouse; corresponding to Ser151 in human) as a potential 14-3-3ε binding site affecting cytoplasmic localization and G2/M control; the work also cites prior human-cell findings where 14-3-3 binding to phosphorylated CDC25B sites drives cytoplasmic localization (he2023ser149isanother pages 1-6). Although this is not a human-only study, it is informative because the residue mapping explicitly links to human numbering and summarizes human-cell literature (he2023ser149isanother pages 1-6).

3.2 Centrosomal activation axis and survivin (2024)

A 2024 Research Square preprint reports that survivin depletion reduces centrosomal Cdk1 level and activity and leads to accumulation of inactive (pT14/pY15) Cdk1; survivin is proposed to facilitate signaling via the Cdc25B–Cdk1 axis at centrosomes (canovas2024survivinmediatesmitotic pages 28-31). Quantitatively, survivin loss reduced the fraction of cells showing a split centrosomal Cdk1 signal by >2-fold (38% vs 15%) (canovas2024survivinmediatesmitotic pages 28-31).

3.3 Redox regulation: a reversible disulfide “switch” protects the catalytic cysteine

CDC25B is unusually sensitive to oxidation at its catalytic cysteine, and multiple biochemical/structural sources support a reversible redox-control mechanism:
- Oxidation of the active-site cysteine by H2O2 is described with a measured second-order rate constant (164 ± 14 M−1 s−1, 20°C, pH 7.0) for Cdc25B (rudolph2005redoxregulationof pages 1-2).
- Structural studies show formation of an intramolecular disulfide between Cys473 (active site) and a “backdoor” cysteine Cys426, accompanied by a P-loop rearrangement that occludes the active site and prevents substrate binding (buhrman2005structuralmechanismof pages 7-8, buhrman2005structuralmechanismof pages 6-7, buhrman2005structuralmechanismof pages 4-6).
- The disulfide form is reported to be rapidly reduced by thioredoxin but not by glutathione, consistent with structural sequestration of the bond and selective cellular reactivation (buhrman2005structuralmechanismof pages 7-8, rudolph2005redoxregulationof pages 1-2).

4) Recent developments (prioritizing 2023–2024)

4.1 2024 translational perspective: CDC25 phosphatases as precision-medicine targets

A 2024 review in Frontiers in Pharmacology positions CDC25 phosphatases (including CDC25B) as proto-oncogenic cell-cycle drivers and discusses inhibitor strategies and precision-medicine framing, emphasizing that rational active-site inhibitor design is challenged by CDC25’s shallow active site and that alternative strategies (interface hotspots, allostery, etc.) may be needed (published Jan 2024; https://doi.org/10.3389/fphar.2024.1324001) (dakilah2024potentialofcdc25 pages 8-9, dakilah2024potentialofcdc25 pages 9-10, dakilah2024potentialofcdc25 pages 10-11).

4.2 2024 mechanistic proposal: survivin links centrosomal Cdk1 to CDC25B

The 2024 HeLa-cell preprint expands on a centrosomal model in which survivin influences the CDC25B–Cdk1 activation axis, providing quantitative imaging readouts and biochemical evidence of altered Cdk1 activation status upon survivin depletion (published Feb 2024; https://doi.org/10.21203/rs.3.rs-3949429/v1) (canovas2024survivinmediatesmitotic pages 28-31).

4.3 2023 residue mapping for 14-3-3 binding and localization control

A 2023 bioRxiv preprint identifies an additional potential 14-3-3ε binding site affecting CDC25B localization and MPF activation dynamics, mapping mouse residues to human (Ser149 mouse ↔ Ser151 human) and citing human-cell literature for 14-3-3-driven cytoplasmic localization (published Aug 2023; https://doi.org/10.1101/2023.08.15.553381) (he2023ser149isanother pages 1-6).

5) Current applications and real-world implementations

5.1 CDC25B as a cancer biomarker and therapeutic target

A comprehensive inhibitor review reports high frequencies of CDC25B overexpression across tumor types, including gastric cancer (78%), breast cancer (57%), gliomas (47%), and colorectal cancer (43–67%), among others (abdelwahab2022acomprehensiveoverview pages 2-4). Such prevalence underpins clinical/translational interest in CDC25B as a biomarker and target in oncology (abdelwahab2022acomprehensiveoverview pages 2-4, dakilah2024potentialofcdc25 pages 9-10).

5.2 Small-molecule inhibition strategies (selected examples with quantitative data)

Covalent active-site targeting:
- The natural product HB-21 irreversibly inhibits recombinant human CDC25B with IC50 = 24.25 μM by covalently binding the catalytic Cys473 (Frontiers in Chemistry, Nov 2018; https://doi.org/10.3389/fchem.2018.00531) (zhang2018dualspecificityphosphatasecdc25b pages 1-2). Structural docking figures show HB-21 positioned in the binding cavity with CYS-473 labeled, supporting the proposed mechanism (zhang2018dualspecificityphosphatasecdc25b media 792a4956, zhang2018dualspecificityphosphatasecdc25b media f30089ca).

Quinones and related scaffolds / broader inhibitor landscape:
- A 2022 review compiles many CDC25 inhibitors with potencies spanning submicromolar to micromolar ranges, including adociaquinone B (IC50 ~0.07 μM against CDC25B catalytic domain) and multiple NSC-series compounds with submicromolar activity (Molecules, Apr 2022; https://doi.org/10.3390/molecules27082389) (abdelwahab2022acomprehensiveoverview pages 8-10).
- Menadione (vitamin K3) is discussed as a CDC25-family inhibitor with Ki ~95 ± 3 μM against CDC25B in compiled biochemical data (abdelwahab2022acomprehensiveoverview pages 2-4).

5.3 In vivo preclinical implementation: menadione in gastric cancer models

A 2020 study in Therapeutic Advances in Gastroenterology reports that menadione reduces CDC25B mRNA/protein in gastric cancer cell lines and induces a G2/M arrest signature with increased p-CDK1 and cyclin B1 consistent with an inactive cyclin B–CDK1 complex; in a primate carcinogenesis model, CDC25B mRNA/protein were reported to be ~40% lower in menadione-treated animals by day 960, and in certain prevention groups no tumors developed (published Jan 2020; https://doi.org/10.1177/1756284819895435) (bona2020menadionereducescdc25b pages 6-8).

6) Expert synthesis and analysis (authoritative takeaways)

CDC25B’s most defensible “primary function” is enzymatic activation of CDK1–cyclin B by removal of inhibitory phosphates at Thr14/Tyr15, functioning as a G2/M trigger (“starter”) particularly in a centrosomal initiation model (abdelwahab2022acomprehensiveoverview pages 1-2, abdelwahab2022acomprehensiveoverview pages 2-4, contourgalcera2007whatsnewon pages 1-2).
Catalytic vulnerability (Cys473) is both a regulatory node and a drug target. Redox chemistry (Cys473 oxidation, reversible disulfide with Cys426 reduced by thioredoxin) provides a biochemical basis for both physiological regulation by ROS and the frequent observation that electrophilic/quinone inhibitors act via cysteine reactivity or ROS generation (buhrman2005structuralmechanismof pages 7-8, rudolph2005redoxregulationof pages 1-2, abdelwahab2022acomprehensiveoverview pages 18-20).
Selectivity is intrinsically challenging because the active site is shallow and substrate recognition is distributed across distal interaction surfaces; the 2024 review highlights the need to consider non–active-site strategies (interface hotspots, allostery) alongside catalytic-site inhibitors (dakilah2024potentialofcdc25 pages 8-9, dakilah2024potentialofcdc25 pages 9-10).

7) Key statistics and data (recently surfaced in the evidence set)

Rate constant for CDC25B oxidation by H2O2: 164 ± 14 M−1 s−1 (20°C, pH 7.0) (rudolph2005redoxregulationof pages 1-2).
Cancer overexpression frequencies (compiled): CDC25B up to 78% gastric, 57% breast, 47% glioma, 43–67% colorectal (abdelwahab2022acomprehensiveoverview pages 2-4).
HB-21 inhibition potency: IC50 = 24.25 μM vs recombinant human CDC25B (zhang2018dualspecificityphosphatasecdc25b pages 1-2).
Survivin depletion phenotype (HeLa, 2024 preprint): fraction of cells with split centrosomal Cdk1 signal 38% vs 15% (canovas2024survivinmediatesmitotic pages 28-31).
Menadione effect (primate model): CDC25B mRNA/protein ~40% lower by day 960 in treated animals (bona2020menadionereducescdc25b pages 6-8).

8) Notes on limitations of the retrieved evidence

Some highly relevant 2023–2024 items are preprints (bioRxiv/Research Square) and should be interpreted cautiously until peer-reviewed (canovas2024survivinmediatesmitotic pages 28-31, he2023ser149isanother pages 1-6).
The clinical-trials search did not return a clearly citable ClinicalTrials.gov record in the current tool output; thus, “real-world implementation” evidence here is primarily preclinical/in vivo and translational review based (dakilah2024potentialofcdc25 pages 8-9, bona2020menadionereducescdc25b pages 6-8).

Key cited sources (URLs / publication dates)

Dakilah et al., Frontiers in Pharmacology (Jan 2024): https://doi.org/10.3389/fphar.2024.1324001 (dakilah2024potentialofcdc25 pages 8-9, dakilah2024potentialofcdc25 pages 9-10, dakilah2024potentialofcdc25 pages 10-11)
Cánovas, Research Square (Feb 2024): https://doi.org/10.21203/rs.3.rs-3949429/v1 (canovas2024survivinmediatesmitotic pages 28-31)
He et al., bioRxiv (Aug 2023): https://doi.org/10.1101/2023.08.15.553381 (he2023ser149isanother pages 1-6)
Abdelwahab et al., Molecules (Apr 2022): https://doi.org/10.3390/molecules27082389 (abdelwahab2022acomprehensiveoverview pages 1-2, abdelwahab2022acomprehensiveoverview pages 2-4, abdelwahab2022acomprehensiveoverview pages 8-10, abdelwahab2022acomprehensiveoverview pages 18-20)
Zhang et al., Frontiers in Chemistry (Nov 2018): https://doi.org/10.3389/fchem.2018.00531 (zhang2018dualspecificityphosphatasecdc25b pages 1-2, zhang2018dualspecificityphosphatasecdc25b media 792a4956, zhang2018dualspecificityphosphatasecdc25b media f30089ca)
Buhrman et al., Biochemistry (Mar 2005): https://doi.org/10.1021/bi047449f (buhrman2005structuralmechanismof pages 7-8, buhrman2005structuralmechanismof pages 6-7, buhrman2005structuralmechanismof pages 4-6, buhrman2005structuralmechanismof pages 1-2)
Rudolph, Antioxidants & Redox Signaling (May 2005): https://doi.org/10.1089/ars.2005.7.761 (rudolph2005redoxregulationof pages 1-2, rudolph2005redoxregulationof pages 2-3)
Bona et al., Therapeutic Advances in Gastroenterology (Jan 2020): https://doi.org/10.1177/1756284819895435 (bona2020menadionereducescdc25b pages 6-8)

References

(abdelwahab2022acomprehensiveoverview pages 1-2): Ahmed Bakr Abdelwahab, Eslam Reda El-Sawy, Atef G. Hanna, Denyse Bagrel, and Gilbert Kirsch. A comprehensive overview of the developments of cdc25 phosphatase inhibitors. Molecules, 27:2389, Apr 2022. URL: https://doi.org/10.3390/molecules27082389, doi:10.3390/molecules27082389. This article has 13 citations.
(abdelwahab2022acomprehensiveoverview pages 2-4): Ahmed Bakr Abdelwahab, Eslam Reda El-Sawy, Atef G. Hanna, Denyse Bagrel, and Gilbert Kirsch. A comprehensive overview of the developments of cdc25 phosphatase inhibitors. Molecules, 27:2389, Apr 2022. URL: https://doi.org/10.3390/molecules27082389, doi:10.3390/molecules27082389. This article has 13 citations.
(davidson2023investigationofpin1 pages 30-34): S Davidson. Investigation of pin1 interaction with the cdc25c phosphatase and a novel series of domain-specific ligands. Unknown journal, 2023.
(davidson2023investigationofpin1a pages 30-34): S Davidson. Investigation of pin1 interaction with the cdc25c phosphatase and a novel series of domain-specific ligands. Unknown journal, 2023.
(davidson2023investigationofpin1a pages 34-37): S Davidson. Investigation of pin1 interaction with the cdc25c phosphatase and a novel series of domain-specific ligands. Unknown journal, 2023.
(liu2020theroleof pages 2-3): Kai Liu, Minying Zheng, Rui Lu, Jia-Xing Du, Qi Zhao, Zugui Li, Yuwei Li, and Shiwu Zhang. The role of cdc25c in cell cycle regulation and clinical cancer therapy: a systematic review. Cancer Cell International, Jun 2020. URL: https://doi.org/10.1186/s12935-020-01304-w, doi:10.1186/s12935-020-01304-w. This article has 332 citations and is from a peer-reviewed journal.
(zhang2018dualspecificityphosphatasecdc25b pages 1-2): Shoude Zhang, Qiangqiang Jia, Qiang Gao, Xueru Fan, Yuxin Weng, and Zhanhai Su. Dual-specificity phosphatase cdc25b was inhibited by natural product hb-21 through covalently binding to the active site. Frontiers in Chemistry, Nov 2018. URL: https://doi.org/10.3389/fchem.2018.00531, doi:10.3389/fchem.2018.00531. This article has 12 citations.
(canovas2024survivinmediatesmitotic pages 28-31): Pedro M. Cánovas. Survivin mediates mitotic onset in hela cells through activation of the cdk1-cdc25b axis. Research Square, Feb 2024. URL: https://doi.org/10.21203/rs.3.rs-3949429/v1, doi:10.21203/rs.3.rs-3949429/v1. This article has 2 citations.
(contourgalcera2007whatsnewon pages 1-2): Marie-Odile Contour-Galcera, Alban Sidhu, Grégoire Prévost, Dennis Bigg, and Bernard Ducommun. What's new on cdc25 phosphatase inhibitors. Pharmacology & therapeutics, 115 1:1-12, Jul 2007. URL: https://doi.org/10.1016/j.pharmthera.2007.03.009, doi:10.1016/j.pharmthera.2007.03.009. This article has 88 citations and is from a domain leading peer-reviewed journal.
(he2023ser149isanother pages 1-6): Wen-Ning He, Hai-Yao Pang, Yan-Jun Hou, Shao-Qing Feng, Hui-Ling Zhang, Wen-Xiu Guo, Ru Liu, and Jun Meng. Ser149 is another potential 14-3-3 ε binding site of cdc25b in the g2/m transition of mouse fertilized eggs. BioRxiv, Aug 2023. URL: https://doi.org/10.1101/2023.08.15.553381, doi:10.1101/2023.08.15.553381. This article has 0 citations.
(bona2020menadionereducescdc25b pages 6-8): Amanda Braga Bona, Danielle Queiroz Calcagno, Helem Ferreira Ribeiro, José Augusto Pereira Carneiro Muniz, Giovanny Rebouças Pinto, Carlos Alberto Machado Rocha, Antonio Carlos Cunha Lacreta Junior, Paulo Pimentel de Assumpção, Juan Antonio Rey Herranz, and Rommel Rodriguez Burbano. Menadione reduces cdc25b expression and promotes tumor shrinkage in gastric cancer. Therapeutic Advances in Gastroenterology, Jan 2020. URL: https://doi.org/10.1177/1756284819895435, doi:10.1177/1756284819895435. This article has 16 citations and is from a peer-reviewed journal.
(dakilah2024potentialofcdc25 pages 8-9): Ibraheem Dakilah, Amani Harb, Eman Abu-Gharbieh, Waseem El-Huneidi, Jalal Taneera, Rifat Hamoudi, Mohammed H. Semreen, and Yasser Bustanji. Potential of cdc25 phosphatases in cancer research and treatment: key to precision medicine. Frontiers in Pharmacology, Jan 2024. URL: https://doi.org/10.3389/fphar.2024.1324001, doi:10.3389/fphar.2024.1324001. This article has 22 citations.
(abdelwahab2022acomprehensiveoverview pages 8-10): Ahmed Bakr Abdelwahab, Eslam Reda El-Sawy, Atef G. Hanna, Denyse Bagrel, and Gilbert Kirsch. A comprehensive overview of the developments of cdc25 phosphatase inhibitors. Molecules, 27:2389, Apr 2022. URL: https://doi.org/10.3390/molecules27082389, doi:10.3390/molecules27082389. This article has 13 citations.
(rudolph2005redoxregulationof pages 1-2): Johannes Rudolph. Redox regulation of the cdc25 phosphatases. Antioxidants & redox signaling, 7 5-6:761-7, May 2005. URL: https://doi.org/10.1089/ars.2005.7.761, doi:10.1089/ars.2005.7.761. This article has 77 citations and is from a domain leading peer-reviewed journal.
(buhrman2005structuralmechanismof pages 7-8): Greg Buhrman, Benjamin Parker, Jungsan Sohn, Johannes Rudolph, and Carla Mattos. Structural mechanism of oxidative regulation of the phosphatase cdc25b via an intramolecular disulfide bond. Biochemistry, 44 14:5307-16, Mar 2005. URL: https://doi.org/10.1021/bi047449f, doi:10.1021/bi047449f. This article has 131 citations and is from a peer-reviewed journal.
(buhrman2005structuralmechanismof pages 6-7): Greg Buhrman, Benjamin Parker, Jungsan Sohn, Johannes Rudolph, and Carla Mattos. Structural mechanism of oxidative regulation of the phosphatase cdc25b via an intramolecular disulfide bond. Biochemistry, 44 14:5307-16, Mar 2005. URL: https://doi.org/10.1021/bi047449f, doi:10.1021/bi047449f. This article has 131 citations and is from a peer-reviewed journal.
(buhrman2005structuralmechanismof pages 4-6): Greg Buhrman, Benjamin Parker, Jungsan Sohn, Johannes Rudolph, and Carla Mattos. Structural mechanism of oxidative regulation of the phosphatase cdc25b via an intramolecular disulfide bond. Biochemistry, 44 14:5307-16, Mar 2005. URL: https://doi.org/10.1021/bi047449f, doi:10.1021/bi047449f. This article has 131 citations and is from a peer-reviewed journal.
(dakilah2024potentialofcdc25 pages 9-10): Ibraheem Dakilah, Amani Harb, Eman Abu-Gharbieh, Waseem El-Huneidi, Jalal Taneera, Rifat Hamoudi, Mohammed H. Semreen, and Yasser Bustanji. Potential of cdc25 phosphatases in cancer research and treatment: key to precision medicine. Frontiers in Pharmacology, Jan 2024. URL: https://doi.org/10.3389/fphar.2024.1324001, doi:10.3389/fphar.2024.1324001. This article has 22 citations.
(dakilah2024potentialofcdc25 pages 10-11): Ibraheem Dakilah, Amani Harb, Eman Abu-Gharbieh, Waseem El-Huneidi, Jalal Taneera, Rifat Hamoudi, Mohammed H. Semreen, and Yasser Bustanji. Potential of cdc25 phosphatases in cancer research and treatment: key to precision medicine. Frontiers in Pharmacology, Jan 2024. URL: https://doi.org/10.3389/fphar.2024.1324001, doi:10.3389/fphar.2024.1324001. This article has 22 citations.
(zhang2018dualspecificityphosphatasecdc25b media 792a4956): Shoude Zhang, Qiangqiang Jia, Qiang Gao, Xueru Fan, Yuxin Weng, and Zhanhai Su. Dual-specificity phosphatase cdc25b was inhibited by natural product hb-21 through covalently binding to the active site. Frontiers in Chemistry, Nov 2018. URL: https://doi.org/10.3389/fchem.2018.00531, doi:10.3389/fchem.2018.00531. This article has 12 citations.
(zhang2018dualspecificityphosphatasecdc25b media f30089ca): Shoude Zhang, Qiangqiang Jia, Qiang Gao, Xueru Fan, Yuxin Weng, and Zhanhai Su. Dual-specificity phosphatase cdc25b was inhibited by natural product hb-21 through covalently binding to the active site. Frontiers in Chemistry, Nov 2018. URL: https://doi.org/10.3389/fchem.2018.00531, doi:10.3389/fchem.2018.00531. This article has 12 citations.
(abdelwahab2022acomprehensiveoverview pages 18-20): Ahmed Bakr Abdelwahab, Eslam Reda El-Sawy, Atef G. Hanna, Denyse Bagrel, and Gilbert Kirsch. A comprehensive overview of the developments of cdc25 phosphatase inhibitors. Molecules, 27:2389, Apr 2022. URL: https://doi.org/10.3390/molecules27082389, doi:10.3390/molecules27082389. This article has 13 citations.
(buhrman2005structuralmechanismof pages 1-2): Greg Buhrman, Benjamin Parker, Jungsan Sohn, Johannes Rudolph, and Carla Mattos. Structural mechanism of oxidative regulation of the phosphatase cdc25b via an intramolecular disulfide bond. Biochemistry, 44 14:5307-16, Mar 2005. URL: https://doi.org/10.1021/bi047449f, doi:10.1021/bi047449f. This article has 131 citations and is from a peer-reviewed journal.
(rudolph2005redoxregulationof pages 2-3): Johannes Rudolph. Redox regulation of the cdc25 phosphatases. Antioxidants & redox signaling, 7 5-6:761-7, May 2005. URL: https://doi.org/10.1089/ars.2005.7.761, doi:10.1089/ars.2005.7.761. This article has 77 citations and is from a domain leading peer-reviewed journal.

Citations

abdelwahab2022acomprehensiveoverview pages 2-4
canovas2024survivinmediatesmitotic pages 28-31
rudolph2005redoxregulationof pages 1-2
abdelwahab2022acomprehensiveoverview pages 8-10
abdelwahab2022acomprehensiveoverview pages 1-2
liu2020theroleof pages 2-3
contourgalcera2007whatsnewon pages 1-2
buhrman2005structuralmechanismof pages 7-8
buhrman2005structuralmechanismof pages 6-7
buhrman2005structuralmechanismof pages 4-6
abdelwahab2022acomprehensiveoverview pages 18-20
buhrman2005structuralmechanismof pages 1-2
rudolph2005redoxregulationof pages 2-3
https://doi.org/10.3389/fphar.2024.1324001
https://doi.org/10.21203/rs.3.rs-3949429/v1
https://doi.org/10.1101/2023.08.15.553381
https://doi.org/10.3389/fchem.2018.00531
https://doi.org/10.3390/molecules27082389
https://doi.org/10.1177/1756284819895435
https://doi.org/10.1021/bi047449f
https://doi.org/10.1089/ars.2005.7.761
https://doi.org/10.3390/molecules27082389,
https://doi.org/10.1186/s12935-020-01304-w,
https://doi.org/10.3389/fchem.2018.00531,
https://doi.org/10.21203/rs.3.rs-3949429/v1,
https://doi.org/10.1016/j.pharmthera.2007.03.009,
https://doi.org/10.1101/2023.08.15.553381,
https://doi.org/10.1177/1756284819895435,
https://doi.org/10.3389/fphar.2024.1324001,
https://doi.org/10.1089/ars.2005.7.761,
https://doi.org/10.1021/bi047449f,

📄 View Raw YAML

id: P30305
gene_symbol: CDC25B
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CDC25B (M-phase inducer phosphatase 2) is a dual-specificity phosphatase (EC 3.1.3.48) that
  activates cyclin-dependent kinases by removing inhibitory phosphates at Thr14 and Tyr15.
  Its primary substrate is CDK1-cyclin B, and it functions as a "starter phosphatase" that
  initiates mitotic entry at the centrosome during the G2/M transition. CDC25B contains a
  conserved C-terminal catalytic domain with the HCX5R motif (catalytic Cys473) and a
  divergent N-terminal regulatory domain. The enzyme is regulated by phosphorylation-dependent
  14-3-3 protein binding (which controls nucleocytoplasmic shuttling), checkpoint kinases
  (CHEK1, MAPKAPK2), and redox-dependent inactivation via an intramolecular disulfide bond
  between Cys473 and Cys426. CDC25B localizes to the centrosome and spindle poles during
  mitosis and shuttles between nucleus and cytoplasm during interphase. It is overexpressed
  in many cancers and is considered a proto-oncogene.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CDC25B shuttles between nucleus and cytoplasm. 14-3-3 binding sequesters it in the
        cytoplasm during interphase, but it translocates to the nucleus as part of its
        activation cycle. Multiple studies confirm nuclear localization.
      action: ACCEPT
      reason: >-
        IBA annotation is well supported. CDC25B is known to shuttle between nucleus and
        cytoplasm, with nuclear localization being part of its functional cycle for
        activating CDK1-cyclin B complexes (PMID:15173315, PMID:12764136). UniProt subcellular
        location also describes centrosomal and spindle pole localization, both of which
        require transit through the nucleus/cytoplasm.
      supported_by:
        - reference_id: PMID:15173315
          supporting_text: >-
            Binding of 14-3-3beta but not 14-3-3sigma controls the cytoplasmic localization
            of CDC25B
        - reference_id: PMID:12764136
          supporting_text: >-
            14-3-3 acts as an intramolecular bridge to regulate cdc25B localization and activity

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CDC25B is present in the cytoplasm, where it is sequestered by 14-3-3 proteins
        during interphase. It also functions at the centrosome, which is in the cytoplasm.
      action: ACCEPT
      reason: >-
        IBA annotation is well supported. CDC25B localizes to cytoplasm during interphase
        via 14-3-3 binding and functions at the centrosome (a cytoplasmic structure) during
        the G2/M transition (PMID:15128871, PMID:15908796).
      supported_by:
        - reference_id: PMID:15173315
          supporting_text: >-
            Binding of 14-3-3beta but not 14-3-3sigma controls the cytoplasmic localization
            of CDC25B

  - term:
      id: GO:0000086
      label: G2/M transition of mitotic cell cycle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CDC25B is a key regulator of the G2/M transition, functioning as a "starter
        phosphatase" that initiates activation of CDK1-cyclin B at the centrosome.
      action: ACCEPT
      reason: >-
        This is one of the most well-established functions of CDC25B. The IBA annotation
        reflects the conserved core function across species. Multiple primary studies
        confirm CDC25B drives G2/M transition through dephosphorylation of CDK1
        (PMID:20360007, PMID:1836978, PMID:17332740).
      supported_by:
        - reference_id: PMID:20360007
          supporting_text: >-
            Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation
            of Cdk1-cyclin B complexes, whereas repression of these phosphatases by short
            hairpin RNA has a reverse effect
        - reference_id: PMID:1836978
          supporting_text: >-
            cdc25A and cdc25B display endogenous tyrosine phosphatase activity that is
            stimulated several-fold, in the absence of cdc2, by stoichiometric addition
            of either cyclin B1 or B2

  - term:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CDC25B is a dual-specificity phosphatase that removes phosphates from both
        phosphotyrosine and phosphothreonine residues on CDKs. The protein tyrosine
        phosphatase activity annotation captures the tyrosine phosphatase component.
      action: ACCEPT
      reason: >-
        IBA annotation is correct. CDC25B dephosphorylates Tyr15 (and Thr14) on CDK1.
        The original characterization demonstrated endogenous tyrosine phosphatase activity
        (PMID:1836978). EC 3.1.3.48 classifies it as a protein-tyrosine-phosphatase.
        While CDC25B is technically a dual-specificity phosphatase, the protein tyrosine
        phosphatase activity term is appropriate since it does remove phosphotyrosine.
      supported_by:
        - reference_id: PMID:1836978
          supporting_text: >-
            cdc25A and cdc25B display endogenous tyrosine phosphatase activity

  - term:
      id: GO:0010971
      label: positive regulation of G2/M transition of mitotic cell cycle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CDC25B positively regulates the G2/M transition by dephosphorylating and
        activating CDK1-cyclin B complexes. This is the core evolved function.
      action: ACCEPT
      reason: >-
        This annotation accurately captures CDC25B's role as a positive regulator
        of mitotic entry. CDC25B dephosphorylation of CDK1 promotes G2/M transition
        (PMID:20360007, PMID:1836978).
      supported_by:
        - reference_id: PMID:20360007
          supporting_text: >-
            Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation
            of Cdk1-cyclin B complexes

  - term:
      id: GO:0110032
      label: positive regulation of G2/MI transition of meiotic cell cycle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        CDC25B has been implicated in meiotic cell cycle regulation. UniProt lists
        GO annotations for oocyte maturation and female meiosis I (IEA from Ensembl),
        consistent with a conserved role in meiotic G2/M transition.
      action: ACCEPT
      reason: >-
        IBA annotations have undergone phylogenetic review and are generally at the right
        level of specificity. CDC25B is known to function in oocyte maturation and meiotic
        cell cycle entry in vertebrates, consistent with this annotation. UniProt lists
        IEA annotations for female meiosis I and oocyte maturation based on Ensembl data.

  - term:
      id: GO:0000922
      label: spindle pole
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        CDC25B localizes to spindle poles during mitosis, as demonstrated by
        immunofluorescence with phospho-specific antibodies.
      action: ACCEPT
      reason: >-
        This IEA annotation is confirmed by direct experimental evidence. UniProt
        explicitly lists spindle pole as a subcellular location based on PMID:15908796.
        The IDA annotation for the same term (below) provides the experimental backing.
      supported_by:
        - reference_id: PMID:15908796
          supporting_text: >-
            CDC25B phosphorylated by pEg3 localizes to the centrosome and the spindle
            poles at mitosis

  - term:
      id: GO:0004721
      label: phosphoprotein phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CDC25B has phosphoprotein phosphatase activity, dephosphorylating CDK1 at
        inhibitory Thr14 and Tyr15 residues.
      action: ACCEPT
      reason: >-
        This IEA annotation from UniProt keyword mapping is correct. CDC25B is
        classified as EC 3.1.3.48, a protein-tyrosine-phosphatase, and its function
        is to dephosphorylate CDK1. This broader term encompasses the more specific
        protein tyrosine phosphatase activity also annotated.
      supported_by:
        - reference_id: PMID:20360007
          supporting_text: >-
            dephosphorylation is catalyzed by the dual specific Cdc25 phosphatases

  - term:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate IEA annotation for protein tyrosine phosphatase activity from
        combined automated methods.
      action: ACCEPT
      reason: >-
        Same term as the IBA annotation above; this IEA confirms via automated
        methods what is well established experimentally. CDC25B is classified as
        EC 3.1.3.48 and has demonstrated tyrosine phosphatase activity (PMID:1836978).

  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        CDC25B localizes to the centrosome, where it initiates activation of CDK1-cyclin B
        at the G2/M transition.
      action: ACCEPT
      reason: >-
        IEA annotation is well supported by experimental data. UniProt lists centrosome
        as a subcellular location with experimental evidence from PMID:15128871,
        PMID:15311285, and PMID:15908796. CDC25B functions as a "starter phosphatase"
        at the centrosome.
      supported_by:
        - reference_id: PMID:15908796
          supporting_text: >-
            CDC25B phosphorylated by pEg3 localizes to the centrosome and the spindle
            poles at mitosis

  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CDC25B is a phosphatase (hydrolase) that cleaves phosphoester bonds on CDK substrates.
      action: ACCEPT
      reason: >-
        This is a very broad parent term for the more specific phosphatase activities
        also annotated. While not very informative on its own, it is not incorrect
        as phosphatases are hydrolases. The IEA from keyword mapping is acceptable
        as a broader classification.

  - term:
      id: GO:0051301
      label: cell division
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        CDC25B is involved in cell division through its role in activating CDK1-cyclin B
        for mitotic entry and its requirement for cytokinesis.
      action: ACCEPT
      reason: >-
        This IEA from UniProt keyword mapping is correct. CDC25B promotes cell division
        through its role at G2/M transition and its requirement for abscission during
        cytokinesis (PMID:17332740). This broad term encompasses both functions.
      supported_by:
        - reference_id: PMID:17332740
          supporting_text: >-
            PRK2 is required for abscission of the midbody at the end of the cell
            division cycle and for phosphorylation and activation of Cdc25B

  - term:
      id: GO:1902751
      label: positive regulation of cell cycle G2/M phase transition
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        CDC25B positively regulates the G2/M phase transition by dephosphorylating CDK1.
      action: ACCEPT
      reason: >-
        This IEA annotation from InterPro mapping is correct and consistent with
        the IBA and IDA annotations for GO:0010971 (positive regulation of G2/M
        transition of mitotic cell cycle). This is the core function of CDC25B.

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10713667
    review:
      summary: >-
        PMID:10713667 demonstrates specific interaction between 14-3-3 isoforms (particularly
        zeta and eta) and CDC25B. This is a functionally significant interaction regulating
        CDC25B localization and activity.
      action: MODIFY
      reason: >-
        The interaction with 14-3-3 proteins is well documented and functionally significant,
        but "protein binding" is too vague per curation guidelines. The interaction with
        14-3-3 proteins should be annotated with a more specific term. CDC25B binds 14-3-3
        via phosphoserine motifs, and this regulates its subcellular localization and activity.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:10713667
          supporting_text: >-
            CDC25 dual-specificity phosphatases are essential regulators that activate
            cyclin-dependent kinases (CDKs) at critical stages of the cell cycle...
            a specific, strong interaction between CDC25B and 14-3-3zeta and eta isoforms
            is revealed by a deletion of 288 residues in the amino-terminal region of CDC25B

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12764136
    review:
      summary: >-
        PMID:12764136 shows 14-3-3 acts as an intramolecular bridge to regulate CDC25B
        localization and activity. This is a specific 14-3-3 binding interaction.
      action: MODIFY
      reason: >-
        Should use a more specific term than protein binding. This study demonstrates
        14-3-3 binding to CDC25B.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:12764136
          supporting_text: >-
            14-3-3 acts as an intramolecular bridge to regulate cdc25B localization and activity

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12766774
    review:
      summary: >-
        PMID:12766774 describes dual phosphorylation controlling Cdc25 phosphatases and
        mitotic entry, likely involving checkpoint kinase-dependent 14-3-3 binding.
      action: MODIFY
      reason: >-
        Protein binding is too vague. The context from the title suggests phosphorylation-
        dependent interactions controlling CDC25 function, likely 14-3-3 binding.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:12766774
          supporting_text: >-
            Dual phosphorylation controls Cdc25 phosphatases and mitotic entry

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12871587
    review:
      summary: >-
        PMID:12871587 is about interaction of 14-3-3 with Bid during seizure-induced
        neuronal death. The relevance to CDC25B is unclear from the abstract.
      action: UNDECIDED
      reason: >-
        This paper is primarily about 14-3-3 interaction with Bid in neuronal death
        contexts. It is not clear how this directly supports a CDC25B protein binding
        annotation. Unable to verify relevance without full text access.
      supported_by:
        - reference_id: PMID:12871587
          supporting_text: >-
            Interaction of 14-3-3 with Bid during seizure-induced neuronal death

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15173315
    review:
      summary: >-
        PMID:15173315 demonstrates 14-3-3beta binding to CDC25B controls cytoplasmic
        localization. This is a specific and functionally relevant interaction.
      action: MODIFY
      reason: >-
        Should use a more specific term. This study specifically examines 14-3-3 binding
        to CDC25B and its effects on subcellular localization.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:15173315
          supporting_text: >-
            Binding of 14-3-3beta but not 14-3-3sigma controls the cytoplasmic localization
            of CDC25B

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15629715
    review:
      summary: >-
        PMID:15629715 shows MAPKAPK2 phosphorylates CDC25B at Ser323, creating a 14-3-3
        binding site. The interaction demonstrated is between CDC25B and its upstream kinase
        MAPKAPK2 and downstream binding partner 14-3-3.
      action: MODIFY
      reason: >-
        Protein binding is too vague. The CDC25B interaction described involves both
        kinase binding (MAPKAPK2) and 14-3-3 binding. The 14-3-3 binding is the more
        specific annotation.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:15629715
          supporting_text: >-
            MAPKAP kinase-2 is directly responsible for Cdc25B/C phosphorylation and
            14-3-3 binding in vitro and in response to UV-induced DNA damage within
            mammalian cells

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16672277
    review:
      summary: >-
        PMID:16672277 examines amino acids C-terminal to the 14-3-3 binding motif in
        CDC25B that affect 14-3-3 binding efficiency. Specific 14-3-3 interaction study.
      action: MODIFY
      reason: >-
        This is specifically about 14-3-3 binding to CDC25B and should be annotated
        with the more specific term.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:16672277
          supporting_text: >-
            Amino acids C-terminal to the 14-3-3 binding motif in CDC25B affect the
            efficiency of 14-3-3 binding

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26496610
    review:
      summary: >-
        PMID:26496610 is a large-scale interactome study. Protein binding from
        high-throughput studies is generally uninformative without specific partner context.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        High-throughput interactome study. Protein binding annotations from such studies
        do not provide specific functional information about CDC25B interactions.
      supported_by:
        - reference_id: PMID:26496610
          supporting_text: >-
            A human interactome in three quantitative dimensions organized by stoichiometries
            and abundances

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: >-
        PMID:28514442 is a large-scale interactome mapping study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        High-throughput interactome study providing uninformative protein binding annotation.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: >-
            Architecture of the human interactome defines protein communities and disease
            networks

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >-
        PMID:32296183 is a large-scale binary interactome mapping study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        High-throughput interactome study. Generic protein binding annotation is not
        informative for functional annotation.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: >-
            A reference map of the human binary protein interactome

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        PMID:33961781 is a large-scale proteome-scale interactome study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        High-throughput interactome study. Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: >-
            Dual proteome-scale networks reveal cell-specific remodeling of the human
            interactome

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: >-
        PMID:35271311 (OpenCell) is a large-scale endogenous tagging and interactome study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        High-throughput study. Generic protein binding is not informative for CDC25B
        functional annotation.
      supported_by:
        - reference_id: PMID:35271311
          supporting_text: >-
            Endogenous tagging for the cartography of human cellular organization

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:36931259
    review:
      summary: >-
        PMID:36931259 describes a chaperone-like role for 14-3-3 proteins. The interaction
        with CDC25B is a known 14-3-3 client interaction.
      action: MODIFY
      reason: >-
        Should use the more specific 14-3-3 protein binding term. CDC25B is a well-known
        14-3-3 client protein.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:36931259
          supporting_text: >-
            A central chaperone-like role for 14-3-3 proteins in human cells

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: >-
        PMID:40205054 is a large-scale multimodal cell map study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        High-throughput study. Generic protein binding is not informative.
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: >-
            Multimodal cell maps as a foundation for structural and functional genomics

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7644510
    review:
      summary: >-
        PMID:7644510 is one of the original studies demonstrating 14-3-3 association
        with cdc25 phosphatases via yeast two-hybrid screen. This is a functionally
        significant interaction.
      action: MODIFY
      reason: >-
        Should use the more specific 14-3-3 protein binding term. This foundational paper
        identified 14-3-3 epsilon and beta as CDC25B-interacting proteins.
      proposed_replacement_terms:
        - id: GO:0071889
          label: 14-3-3 protein binding
      supported_by:
        - reference_id: PMID:7644510
          supporting_text: >-
            Two members of the 14-3-3 protein family have been isolated in a yeast
            two-hybrid screen designed to identify proteins that interact with the
            human cdc25A and cdc25B phosphatases

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for nuclear localization, consistent with the IBA annotation above.
      action: ACCEPT
      reason: >-
        Consistent with the IBA annotation and known biology of CDC25B nuclear-cytoplasmic
        shuttling.

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for cytoplasmic localization, consistent with the IBA annotation above.
      action: ACCEPT
      reason: >-
        Consistent with the IBA annotation and known cytoplasmic localization of CDC25B
        during interphase via 14-3-3 sequestration.

  - term:
      id: GO:0000086
      label: G2/M transition of mitotic cell cycle
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-69275
    review:
      summary: >-
        TAS annotation from Reactome G2/M Transition pathway. CDC25B is a central
        component of this pathway.
      action: ACCEPT
      reason: >-
        Reactome correctly includes CDC25B in the G2/M transition pathway. This is the
        core biological process for CDC25B.

  - term:
      id: GO:0004721
      label: phosphoprotein phosphatase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-170153
    review:
      summary: >-
        TAS from Reactome pathway for dephosphorylation of nuclear Cyclin B1:phospho-Cdc2
        complexes by Cdc25 phosphatases.
      action: ACCEPT
      reason: >-
        Correctly annotates CDC25B's phosphoprotein phosphatase activity in the context
        of dephosphorylating CDK1-cyclin B complexes in the nucleus.

  - term:
      id: GO:0004721
      label: phosphoprotein phosphatase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-170161
    review:
      summary: >-
        TAS from Reactome pathway for dephosphorylation of cytoplasmic Cyclin B1/B2:
        phospho-Cdc2 complexes specifically by CDC25B.
      action: ACCEPT
      reason: >-
        Correctly annotates CDC25B's phosphoprotein phosphatase activity. Reactome
        R-HSA-170161 specifically names CDC25B as the phosphatase for cytoplasmic
        CDK1-cyclin B dephosphorylation.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9929935
    review:
      summary: >-
        TAS from Reactome pathway CCNA:CDK1 phosphorylates CDC25B, placing CDC25B
        in the nucleoplasm.
      action: ACCEPT
      reason: >-
        CDC25B is phosphorylated by Cyclin A:CDK1 complexes in the nucleus, consistent
        with nucleoplasmic localization during parts of its functional cycle.

  - term:
      id: GO:0004721
      label: phosphoprotein phosphatase activity
    evidence_type: IDA
    original_reference_id: PMID:20360007
    review:
      summary: >-
        PMID:20360007 directly demonstrates that CDC25B has phosphoprotein phosphatase
        activity, dephosphorylating CDK1 to promote assembly and activation of
        CDK1-cyclin B complexes at G2/M.
      action: ACCEPT
      reason: >-
        Direct experimental demonstration (IDA) of CDC25B phosphatase activity.
        The study shows overexpression of CDC25B promotes CDK1-cyclin B assembly
        and activation while knockdown inhibits it (PMID:20360007).
      supported_by:
        - reference_id: PMID:20360007
          supporting_text: >-
            Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation
            of Cdk1-cyclin B complexes, whereas repression of these phosphatases by short
            hairpin RNA has a reverse effect, leading to a substantial decrease in amounts
            of cyclin B-bound Cdk1 in G(2) and mitosis

  - term:
      id: GO:0010971
      label: positive regulation of G2/M transition of mitotic cell cycle
    evidence_type: IDA
    original_reference_id: PMID:20360007
    review:
      summary: >-
        PMID:20360007 directly demonstrates CDC25B positively regulates G2/M transition
        through effects on CDK1-cyclin B complex assembly and activation.
      action: ACCEPT
      reason: >-
        Direct experimental evidence (IDA) confirming CDC25B's role as a positive
        regulator of G2/M transition. Overexpression accelerates G2/M while knockdown
        delays it (PMID:20360007).
      supported_by:
        - reference_id: PMID:20360007
          supporting_text: >-
            Cdc25A and Cdc25B, but not Cdc25C phosphatases have an effect on timing and
            efficiency of cyclin-kinase complex formation

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8863007
    review:
      summary: >-
        TAS from Reactome pathway for p25-bound CDK5 phosphorylation of CDC25B,
        placing CDC25B in the cytosol.
      action: ACCEPT
      reason: >-
        CDC25B is present in the cytosol as part of its nucleocytoplasmic shuttling
        and centrosomal localization cycle. Reactome places it in the cytosol for
        CDK5-mediated phosphorylation.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-170120
    review:
      summary: >-
        TAS from Reactome for translocation of Cdc25B to the cytoplasm, implying
        nucleoplasmic origin.
      action: ACCEPT
      reason: >-
        CDC25B translocates from nucleus to cytoplasm, consistent with nucleoplasmic
        localization before translocation.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-170153
    review:
      summary: >-
        TAS from Reactome for dephosphorylation of nuclear Cyclin B1:phospho-Cdc2
        complexes, placing CDC25B in nucleoplasm.
      action: ACCEPT
      reason: >-
        CDC25B dephosphorylates CDK1-cyclin B complexes in the nucleus, consistent
        with nucleoplasmic localization.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-170159
    review:
      summary: >-
        TAS from Reactome for translocation of Cdc25 to the nucleus.
      action: ACCEPT
      reason: >-
        CDC25B translocates to the nucleus as part of its activation cycle.

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9926524
    review:
      summary: >-
        TAS from Reactome for MITF-M-dependent CDC25B gene expression,
        placing CDC25B in the nucleoplasm.
      action: ACCEPT
      reason: >-
        Consistent with nucleoplasmic localization of CDC25B.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-170120
    review:
      summary: >-
        TAS from Reactome for translocation of Cdc25B to the cytoplasm.
      action: ACCEPT
      reason: >-
        CDC25B translocates to the cytoplasm/cytosol during its regulation cycle,
        where it is sequestered by 14-3-3 proteins.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-170159
    review:
      summary: >-
        TAS from Reactome for translocation of Cdc25 to the nucleus, implying
        cytosolic origin before translocation.
      action: ACCEPT
      reason: >-
        CDC25B is in the cytosol before translocating to the nucleus.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-170161
    review:
      summary: >-
        TAS from Reactome for dephosphorylation of cytoplasmic Cyclin B1/B2:
        phospho-Cdc2 complexes by CDC25B.
      action: ACCEPT
      reason: >-
        CDC25B dephosphorylates CDK1-cyclin B complexes in the cytosol, consistent
        with its centrosomal activation function.

  - term:
      id: GO:0006468
      label: protein phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:17332740
    review:
      summary: >-
        CRITICAL MISANNOTATION: CDC25B is a PHOSPHATASE (EC 3.1.3.48), NOT a kinase.
        UniProt states it "Directly dephosphorylates CDK1 and stimulates its kinase
        activity." PMID:17332740 describes CDC25B as "the phosphatase required for
        activation of mitotic cyclin/Cdk1 complexes" - it dephosphorylates CDK1 to
        activate it. Annotating a phosphatase to "protein phosphorylation" is incorrect.
      action: REMOVE
      reason: >-
        CDC25B is a phosphatase that removes phosphate groups from CDK1. The paper
        PMID:17332740 describes PRK2/PKN2 as the kinase that phosphorylates CDC25B,
        and CDC25B as the phosphatase downstream. The annotation of CDC25B to "protein
        phosphorylation" (GO:0006468) confuses the fact that CDC25B is a substrate of
        phosphorylation with CDC25B performing phosphorylation. CDC25B performs
        dephosphorylation, not phosphorylation.
      supported_by:
        - reference_id: PMID:17332740
          supporting_text: >-
            PRK2 is required for abscission of the midbody at the end of the cell
            division cycle and for phosphorylation and activation of Cdc25B, the
            phosphatase required for activation of mitotic cyclin/Cdk1 complexes at
            the G2/M transition

  - term:
      id: GO:0032467
      label: positive regulation of cytokinesis
    evidence_type: IMP
    original_reference_id: PMID:17332740
    review:
      summary: >-
        PMID:17332740 demonstrates that CDC25B is required for abscission during
        cytokinesis in an ECT2-dependent manner, supporting a role in positive
        regulation of cytokinesis.
      action: KEEP_AS_NON_CORE
      reason: >-
        While the core function of CDC25B is G2/M transition regulation, the role
        in cytokinesis is a secondary function demonstrated by IMP evidence. The
        paper shows PRK2 controls exit from cytokinesis through CDC25B and ECT2
        (PMID:17332740). UniProt also notes CDC25B is "Required for G2/M phases
        of the cell cycle progression and abscission during cytokinesis in a
        ECT2-dependent manner." This is a real but non-core function.
      supported_by:
        - reference_id: PMID:17332740
          supporting_text: >-
            PRK2 is required for abscission of the midbody at the end of the cell
            division cycle and for phosphorylation and activation of Cdc25B

  - term:
      id: GO:0045931
      label: positive regulation of mitotic cell cycle
    evidence_type: IMP
    original_reference_id: PMID:17332740
    review:
      summary: >-
        PMID:17332740 shows CDC25B positively regulates mitotic cell cycle entry
        via PRK2-dependent phosphorylation and activation.
      action: ACCEPT
      reason: >-
        This annotation is correct. CDC25B promotes entry into mitosis by activating
        CDK1-cyclin B complexes. The paper demonstrates PRK2 phosphorylates and
        activates CDC25B for mitotic entry (PMID:17332740). This is consistent
        with the core function of CDC25B.
      supported_by:
        - reference_id: PMID:17332740
          supporting_text: >-
            PRK2 is required for abscission of the midbody at the end of the cell
            division cycle and for phosphorylation and activation of Cdc25B, the
            phosphatase required for activation of mitotic cyclin/Cdk1 complexes at
            the G2/M transition

  - term:
      id: GO:0000086
      label: G2/M transition of mitotic cell cycle
    evidence_type: TAS
    original_reference_id: PMID:12400006
    review:
      summary: >-
        PMID:12400006 describes pEg3 kinase associating with and phosphorylating
        CDC25B, with implications for G2/M cell cycle regulation.
      action: ACCEPT
      reason: >-
        CDC25B's role in G2/M transition is well established. This paper provides
        additional evidence by showing pEg3 kinase regulates CDC25B at the G2/M
        boundary (PMID:12400006).
      supported_by:
        - reference_id: PMID:12400006
          supporting_text: >-
            CDC25B is one of the three CDC25 phosphatase genes identified in human.
            It is thought to regulate the G2/M progression by dephosphorylating and
            activating the CDK/cyclin complexes

  - term:
      id: GO:0000922
      label: spindle pole
    evidence_type: IDA
    original_reference_id: PMID:15908796
    review:
      summary: >-
        PMID:15908796 demonstrates by immunofluorescence with phospho-specific antibodies
        that CDC25B phosphorylated at Ser169 by pEg3 localizes to spindle poles during mitosis.
      action: ACCEPT
      reason: >-
        Direct experimental evidence (IDA) for spindle pole localization. The study
        uses phosphoepitope-specific antibodies to show the phosphorylated form of
        CDC25B at spindle poles during mitosis (PMID:15908796). UniProt also lists
        spindle pole as a confirmed subcellular location.
      supported_by:
        - reference_id: PMID:15908796
          supporting_text: >-
            using phosphoepitope-specific antibodies we show that serine 169 is
            phosphorylated in vivo, that this phosphorylated form of CDC25B
            accumulates during mitosis, and is localized to the centrosomes

  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IDA
    original_reference_id: PMID:15908796
    review:
      summary: >-
        PMID:15908796 directly demonstrates CDC25B localization to the centrosome
        during mitosis, confirmed by phospho-specific antibodies for Ser169.
      action: ACCEPT
      reason: >-
        Direct experimental evidence (IDA) for centrosomal localization. CDC25B
        functions as a "starter phosphatase" at the centrosome, and this is one of
        the key localization sites for its G2/M function. UniProt confirms centrosome
        as a subcellular location with multiple supporting references.
      supported_by:
        - reference_id: PMID:15908796
          supporting_text: >-
            CDC25B phosphorylated by pEg3 localizes to the centrosome and the spindle
            poles at mitosis

  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IPI
    original_reference_id: PMID:12400006
    review:
      summary: >-
        PMID:12400006 demonstrates that pEg3 (MELK) kinase physically associates with
        CDC25B in vitro and in vivo, and phosphorylates CDC25B at Ser323.
      action: ACCEPT
      reason: >-
        CDC25B binds multiple protein kinases including pEg3/MELK (PMID:12400006),
        AURKA (PMID:15128871), CHEK1 (PMID:15311285), and MAPKAPK2 (PMID:15629715).
        These are functionally significant interactions as CDC25B is a substrate
        of these kinases. Protein kinase binding is an appropriate term.
      supported_by:
        - reference_id: PMID:12400006
          supporting_text: >-
            pEg3 is also able to specifically associate with CDC25B in vitro and in vivo

  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IPI
    original_reference_id: PMID:15908796
    review:
      summary: >-
        PMID:15908796 confirms pEg3 kinase interaction with CDC25B, showing
        phosphorylation-dependent localization effects.
      action: ACCEPT
      reason: >-
        Confirms protein kinase binding between pEg3/MELK and CDC25B. The study
        shows pEg3 phosphorylates CDC25B at Ser169 and this interaction controls
        centrosomal localization (PMID:15908796).
      supported_by:
        - reference_id: PMID:15908796
          supporting_text: >-
            we study the phosphorylation of CDC25B at mitosis by the kinase pEg3,
            a member of the KIN1/PAR-1/MARK family

  - term:
      id: GO:0000278
      label: mitotic cell cycle
    evidence_type: TAS
    original_reference_id: PMID:1836978
    review:
      summary: >-
        PMID:1836978 is the original characterization of CDC25B showing it has
        tyrosine phosphatase activity activated by B-type cyclins and is involved
        in the mitotic cell cycle.
      action: ACCEPT
      reason: >-
        Foundational paper establishing CDC25B as a mitotic cell cycle regulator.
        The study shows CDC25B is activated by cyclin B1/B2 and functions in
        mitotic regulation (PMID:1836978).
      supported_by:
        - reference_id: PMID:1836978
          supporting_text: >-
            cdc25A and cdc25B display endogenous tyrosine phosphatase activity that is
            stimulated several-fold, in the absence of cdc2, by stoichiometric addition
            of either cyclin B1 or B2 but not A or D1

  - term:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
    evidence_type: TAS
    original_reference_id: PMID:1836978
    review:
      summary: >-
        PMID:1836978 demonstrates endogenous tyrosine phosphatase activity of CDC25B
        that is stimulated by B-type cyclins.
      action: ACCEPT
      reason: >-
        The original study demonstrating CDC25B has tyrosine phosphatase activity.
        This is the core enzymatic activity of CDC25B (PMID:1836978).
      supported_by:
        - reference_id: PMID:1836978
          supporting_text: >-
            cdc25A and cdc25B display endogenous tyrosine phosphatase activity

  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: TAS
    original_reference_id: PMID:8276402
    review:
      summary: >-
        PMID:8276402 maps CDC25A and CDC25B chromosomal locations and discusses
        their potential as oncogenes due to their role in promoting cell division.
        No direct experimental evidence for cell proliferation regulation is provided.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        PMID:8276402 is a chromosome mapping study that only mentions the potential
        role of CDC25B as an oncogene based on its function in cell division. It
        does not directly demonstrate positive regulation of cell population
        proliferation. While CDC25B overexpression is associated with cancer, this
        is a pleiotropic effect rather than a core functional annotation.
      supported_by:
        - reference_id: PMID:8276402
          supporting_text: >-
            the genes encoding these phosphatases may be suspected as potential
            oncogenes due to their role in promoting cell division

  - term:
      id: GO:0000278
      label: mitotic cell cycle
    evidence_type: TAS
    original_reference_id: PMID:9188863
    review:
      summary: >-
        PMID:9188863 identifies alternative splice variants of CDC25B and shows
        their cell cycle regulation in G2 phase.
      action: ACCEPT
      reason: >-
        The study confirms CDC25B expression is cell cycle regulated, peaking
        in G2, and that the variants function as mitotic inducers (PMID:9188863).
      supported_by:
        - reference_id: PMID:9188863
          supporting_text: >-
            In primary fibroblasts and in HeLa cells the CDC25B expression is cell
            cycle regulated, reaching a maximum in G2-phase

  - term:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
    evidence_type: TAS
    original_reference_id: PMID:9188863
    review:
      summary: >-
        PMID:9188863 confirms CDC25B splice variants have tyrosine phosphatase
        activity with different levels of activity.
      action: ACCEPT
      reason: >-
        The study demonstrates all three CDC25B splice variants have phosphatase
        activity (PMID:9188863), confirming the protein tyrosine phosphatase annotation.
      supported_by:
        - reference_id: PMID:9188863
          supporting_text: >-
            In vitro, CDC25B1 phosphatase is slightly more active than CDC25B2 and B3

references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
      Location vocabulary mapping, accompanied by conservative changes to GO
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10713667
    title: Specific interaction between 14-3-3 isoforms and the human CDC25B
      phosphatase.
    findings:
      - statement: >-
          CDC25B interacts specifically with 14-3-3 zeta and eta isoforms through a
          high-affinity binding site requiring Ser323 integrity.
  - id: PMID:12400006
    title: 'Human pEg3 kinase associates with and phosphorylates CDC25B phosphatase:
      a potential role for pEg3 in cell cycle regulation.'
    findings:
      - statement: >-
          pEg3/MELK kinase phosphorylates CDC25B at Ser323 and physically associates
          with it in vitro and in vivo, regulating G2/M progression.
  - id: PMID:12764136
    title: 14-3-3 acts as an intramolecular bridge to regulate cdc25B
      localization and activity.
    findings:
      - statement: >-
          14-3-3 binding to CDC25B acts as an intramolecular bridge controlling
          localization and activity.
  - id: PMID:12766774
    title: Dual phosphorylation controls Cdc25 phosphatases and mitotic entry.
    findings:
      - statement: >-
          Dual phosphorylation controls CDC25 phosphatase localization and mitotic entry
          through 14-3-3 binding.
  - id: PMID:12871587
    title: Interaction of 14-3-3 with Bid during seizure-induced neuronal death.
    findings: []
  - id: PMID:15173315
    title: 'Binding of 14-3-3beta but not 14-3-3sigma controls the cytoplasmic localization
      of CDC25B: binding site preferences of 14-3-3 subtypes and the subcellular localization
      of CDC25B.'
    findings:
      - statement: >-
          14-3-3beta binding controls cytoplasmic localization of CDC25B while
          14-3-3sigma does not.
  - id: PMID:15629715
    title: MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the
      G2/M transition and S phase progression in response to UV irradiation.
    findings:
      - statement: >-
          MAPKAPK2 phosphorylates CDC25B/C creating 14-3-3 binding sites as part of
          the DNA damage checkpoint response.
  - id: PMID:15908796
    title: CDC25B phosphorylated by pEg3 localizes to the centrosome and the
      spindle poles at mitosis.
    findings:
      - statement: >-
          pEg3/MELK phosphorylates CDC25B at Ser169 and the phosphorylated form
          localizes to centrosomes and spindle poles during mitosis.
  - id: PMID:16672277
    title: Amino acids C-terminal to the 14-3-3 binding motif in CDC25B affect
      the efficiency of 14-3-3 binding.
    findings:
      - statement: >-
          Residues C-terminal to the 14-3-3 binding motif in CDC25B modulate
          14-3-3 binding efficiency.
  - id: PMID:17332740
    title: Rho GTPases regulate PRK2/PKN2 to control entry into mitosis and exit
      from cytokinesis.
    findings:
      - statement: >-
          PRK2/PKN2 phosphorylates and activates CDC25B for mitotic entry and
          CDC25B is required for abscission during cytokinesis in an ECT2-dependent manner.
  - id: PMID:1836978
    title: 'Specific activation of cdc25 tyrosine phosphatases by B-type cyclins:
      evidence for multiple roles of mitotic cyclins.'
    findings:
      - statement: >-
          CDC25B has endogenous tyrosine phosphatase activity stimulated by cyclin B1/B2
          and was originally identified as a mitotic regulator.
  - id: PMID:20360007
    title: Cdc25 phosphatases are required for timely assembly of CDK1-cyclin B
      at the G2/M transition.
    findings:
      - statement: >-
          CDC25A and CDC25B promote timely assembly and activation of CDK1-cyclin B
          complexes at G2/M. Knockdown delays complex formation.
  - id: PMID:26496610
    title: A human interactome in three quantitative dimensions organized by
      stoichiometries and abundances.
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the
      human interactome.
    findings: []
  - id: PMID:35271311
    title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
    findings: []
  - id: PMID:36931259
    title: A central chaperone-like role for 14-3-3 proteins in human cells.
    findings: []
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional
      genomics.
    findings: []
  - id: PMID:7644510
    title: 14-3-3 proteins associate with cdc25 phosphatases.
    findings:
      - statement: >-
          14-3-3 epsilon and beta proteins were identified as CDC25A/B interacting
          partners by yeast two-hybrid screen.
  - id: PMID:8276402
    title: Chromosome mapping of human CDC25A and CDC25B phosphatases.
    findings:
      - statement: >-
          CDC25B maps to chromosome 20p13. The paper discusses potential oncogenic
          role but provides no direct proliferation evidence.
  - id: PMID:9188863
    title: Alternative splicing of the human CDC25B tyrosine phosphatase.
      Possible implications for growth control?
    findings:
      - statement: >-
          Three CDC25B splice variants (B1, B2, B3) identified with different
          phosphatase activities. Expression peaks in G2 phase.
  - id: Reactome:R-HSA-170120
    title: Translocation of Cdc25B to the cytoplasm
    findings: []
  - id: Reactome:R-HSA-170153
    title: Dephosphorylation of nuclear Cyclin B1:phospho-Cdc2 (Thr 14, Tyr15)
      complexes by Cdc25 phosphatases
    findings: []
  - id: Reactome:R-HSA-170159
    title: Translocation of Cdc25 to the nucleus
    findings: []
  - id: Reactome:R-HSA-170161
    title: Dephosphorylation of cytoplasmic Cyclin B1/B2:phospho-Cdc2 (Thr 14,
      Tyr 15) complexes by CDC25B
    findings: []
  - id: Reactome:R-HSA-69275
    title: G2/M Transition
    findings: []
  - id: Reactome:R-HSA-8863007
    title: p25-bound CDK5 phosphorylates CDC25B
    findings: []
  - id: Reactome:R-HSA-9926524
    title: MITF-M-dependent CDC25B gene expression
    findings: []
  - id: Reactome:R-HSA-9929935
    title: CCNA:CDK1 phosphorylates CDC25B
    findings: []

core_functions:
  - description: >-
      Dual-specificity phosphatase that dephosphorylates CDK1 (at inhibitory Thr14
      and Tyr15) to activate CDK1-cyclin B complexes at the G2/M transition of the
      mitotic cell cycle
    molecular_function:
      id: GO:0004725
      label: protein tyrosine phosphatase activity
    directly_involved_in:
      - id: GO:0010971
        label: positive regulation of G2/M transition of mitotic cell cycle
    locations:
      - id: GO:0005813
        label: centrosome
    supported_by:
      - reference_id: PMID:20360007
        supporting_text: >-
          Cdc25A and Cdc25B, but not Cdc25C phosphatases have an effect on timing
          and efficiency of cyclin-kinase complex formation
      - reference_id: PMID:1836978
        supporting_text: >-
          cdc25A and cdc25B display endogenous tyrosine phosphatase activity that is
          stimulated several-fold, in the absence of cdc2, by stoichiometric addition
          of either cyclin B1 or B2

  - description: >-
      14-3-3 binding regulates CDC25B nucleocytoplasmic shuttling. Phosphorylation
      at Ser323 and Ser375 creates 14-3-3 binding sites that sequester CDC25B in
      the cytoplasm during interphase and in response to DNA damage checkpoint
      activation.
    molecular_function:
      id: GO:0071889
      label: 14-3-3 protein binding
    directly_involved_in:
      - id: GO:0000086
        label: G2/M transition of mitotic cell cycle
    locations:
      - id: GO:0005737
        label: cytoplasm
    supported_by:
      - reference_id: PMID:10713667
        supporting_text: >-
          a specific, strong interaction between CDC25B and 14-3-3zeta and eta isoforms
          is revealed by a deletion of 288 residues in the amino-terminal region of CDC25B
      - reference_id: PMID:15629715
        supporting_text: >-
          MAPKAP kinase-2 is directly responsible for Cdc25B/C phosphorylation and
          14-3-3 binding in vitro and in response to UV-induced DNA damage within
          mammalian cells

CDC25B

Gene Description

Existing Annotations Review

Core Functions

Dual-specificity phosphatase that dephosphorylates CDK1 (at inhibitory Thr14 and Tyr15) to activate CDK1-cyclin B complexes at the G2/M transition of the mitotic cell cycle

14-3-3 binding regulates CDC25B nucleocytoplasmic shuttling. Phosphorylation at Ser323 and Ser375 creates 14-3-3 binding sites that sequester CDC25B in the cytoplasm during interphase and in response to DNA damage checkpoint activation.

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Research Report: Human CDC25B (UniProt P30305) — Functional Annotation and Translational Relevance

0) Target verification (required)

1) Key concepts and definitions (current understanding)

1.1 CDC25B is a dual-specificity phosphatase (DSP) that activates CDKs

1.2 Catalytic architecture: HCX5R motif and a cysteine-based PTP-like mechanism

1.3 Substrate recognition: shallow active site and distal “hotspot” residues

2) Molecular function and pathway role

2.1 Primary biochemical function: dephosphorylation of inhibitory CDK sites

2.2 Cell-cycle systems role: “starter phosphatase” at the centrosome

3) Regulation and subcellular localization

3.1 Phosphorylation-dependent 14-3-3 binding and nucleocytoplasmic shuttling

3.2 Centrosomal activation axis and survivin (2024)

3.3 Redox regulation: a reversible disulfide “switch” protects the catalytic cysteine

4) Recent developments (prioritizing 2023–2024)

4.1 2024 translational perspective: CDC25 phosphatases as precision-medicine targets

4.2 2024 mechanistic proposal: survivin links centrosomal Cdk1 to CDC25B

4.3 2023 residue mapping for 14-3-3 binding and localization control

5) Current applications and real-world implementations

5.1 CDC25B as a cancer biomarker and therapeutic target

5.2 Small-molecule inhibition strategies (selected examples with quantitative data)

5.3 In vivo preclinical implementation: menadione in gastric cancer models

6) Expert synthesis and analysis (authoritative takeaways)

7) Key statistics and data (recently surfaced in the evidence set)

8) Notes on limitations of the retrieved evidence

Key cited sources (URLs / publication dates)

Citations

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