Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003682 chromatin binding	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 is a well-established histone chaperone that binds core histones H3, H2B, and H4 (PMID:11602260, PMID:16107701), mediates nucleosome assembly/disassembly, and enhances acetylation-dependent chromatin transcription. Chromatin binding is consistent with its histone chaperone function. The IBA annotation is phylogenetically supported and appropriate. Reason: NPM1 directly binds histones and chromatin as part of its histone chaperone activity. PMID:16107701 showed NPM1 enhances acetylation-dependent chromatin transcription, and PMID:11602260 demonstrated histone binding and nucleosome assembly. Chromatin binding is a core function. Supporting Evidence: PMID:16107701 Human histone chaperone nucleophosmin interacts with the core histones H3, H2B, and H4 but that this histone interaction is not sufficient to confer the chaperone activity. PMID:11602260 Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to mediate formation of nucleosome, and to decondense sperm chromatin.
GO:0005654 nucleoplasm	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 is primarily nucleolar but translocates to the nucleoplasm under various conditions including serum starvation, anticancer drug treatment, and DNA damage. UniProt confirms nucleoplasm localization (ECO:0000269\|PubMed:25818168). The IBA annotation is appropriate. Reason: NPM1 is well-documented to localize to the nucleoplasm, particularly under stress conditions. Multiple IDA evidence supports this localization.
GO:0005730 nucleolus	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is mediated by RNA binding activity of the C-terminal domain (PMID:24106084). Multiple IDA annotations confirm nucleolar localization. This is a core localization for NPM1. Reason: Nucleolus is the primary localization of NPM1 and is essential for its core functions in ribosome biogenesis and histone chaperoning.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 is a nucleocytoplasmic shuttling protein. It is found in the cytoplasm both during normal shuttling (PMID:9121481) and aberrantly in AML with NPM1c mutations. IDA evidence from PMID:9121481 confirms cytoplasmic localization. Reason: NPM1 shuttles between nucleus and cytoplasm as part of its function in ribosome export and other transport roles. Cytoplasmic localization is well-established.
GO:0003723 RNA binding	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 binds RNA, particularly rRNA, through its C-terminal domain and intrinsically disordered basic region (PMID:24106084, PMID:12058066). RNA binding is modulated by phosphorylation and is essential for nucleolar localization and ribosome biogenesis. This is a core molecular function of NPM1. Reason: RNA binding is a core function of NPM1 essential for ribosome biogenesis. Well-supported by multiple direct assay experiments. Supporting Evidence: PMID:24106084 Nucleophosmin (NPM1/B23) is a nucleolar protein implicated in growth-associated functions, in which the RNA binding activity of B23 plays essential roles in ribosome biogenesis. PMID:12058066 It has been shown that B23 binds to nucleic acids, digests RNA, and is localized in nucleolar granular components from which preribosomal particles are transported to cytoplasm.
GO:0042393 histone binding	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 binds core histones H3, H2B, and H4 as part of its histone chaperone activity (PMID:11602260, PMID:16107701). Histone binding is a core molecular function of NPM1 and is prerequisite for its nucleosome assembly activity. Reason: Histone binding is a core function of NPM1, directly demonstrated by IDA in PMID:11602260. Supporting Evidence: PMID:11602260 Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to mediate formation of nucleosome, and to decondense sperm chromatin.
GO:0006338 chromatin remodeling	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 functions as a histone chaperone that mediates nucleosome assembly/disassembly and enhances acetylation-dependent chromatin transcription (PMID:16107701). It also decondenses sperm chromatin (PMID:11602260). These activities constitute chromatin remodeling. The IBA annotation is phylogenetically supported and appropriate. Reason: NPM1 is a histone chaperone involved in nucleosome dynamics and chromatin structure changes. Multiple studies support a role in chromatin remodeling. Supporting Evidence: PMID:16107701 Presumably, nucleophosmin disrupts the nucleosomal structure in an acetylation-dependent manner, resulting in the transcriptional activation.
GO:0000055 ribosomal large subunit export from nucleus	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 serves as a rate-limiting nuclear export chaperone for ribosomal subunits (PMID:18809582). It directly binds ribosomal large subunits and mediates their export via CRM1-dependent pathway. PMID:16648475 showed NPM1 is essential for ribosomal protein L5 nuclear export and associates with maturing nuclear 60S ribosomal subunits. This is a core function of NPM1. Reason: Ribosomal large subunit export is a core function of NPM1, directly demonstrated by multiple experimental studies. Supporting Evidence: PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome. PMID:16648475 Direct interaction of NPM with rpL5 mediated the colocalization of NPM with maturing nuclear 60S ribosomal subunits, as well as newly exported and assembled 80S ribosomes and polysomes.
GO:0000056 ribosomal small subunit export from nucleus	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 binds ribosomal small subunits (PMID:18809582) and serves as a nuclear export chaperone for ribosomal subunits. The IBA annotation is phylogenetically supported. Reason: PMID:18809582 demonstrated NPM1 binds both ribosomal large and small subunits and serves as a rate-limiting export chaperone. Supporting Evidence: PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
GO:0005813 centrosome	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 associates with unduplicated centrosomes and dissociates upon CDK2/cyclin E-mediated phosphorylation to initiate centrosome duplication (PMID:11051553). UniProt confirms centrosome localization. Multiple IDA annotations support this. Reason: Centrosome localization is well-established for NPM1 and is functionally important for regulating centrosome duplication. Supporting Evidence: PMID:11051553 NPM/B23 associates specifically with unduplicated centrosomes, and NPM/B23 dissociates from centrosomes by CDK2/cyclin E-mediated phosphorylation.
GO:0010824 regulation of centrosome duplication	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 negatively regulates centrosome duplication by associating with unduplicated centrosomes; its dissociation after phosphorylation by CDK2/cyclin E initiates duplication (PMID:11051553). PLK2 phosphorylation of NPM1 at Ser4 triggers centriole duplication (PMID:20352051). Ran-Crm1 controls NPM1 association with centrosomes (PMID:16041368). This is a core function of NPM1. Reason: Regulation of centrosome duplication is a well-established core function of NPM1, supported by multiple experimental studies in high-impact journals. Supporting Evidence: PMID:11051553 We identified nucleophosmin (NPM/B23) as a substrate of CDK2/cyclin E in centrosome duplication. NPM/B23 associates specifically with unduplicated centrosomes, and NPM/B23 dissociates from centrosomes by CDK2/cyclin E-mediated phosphorylation. PMID:20352051 Plk2 phosphorylates NPM/B23 on serine 4
GO:0042273 ribosomal large subunit biogenesis	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 is essential for ribosomal large subunit biogenesis. It binds the large ribosomal subunit (PMID:18809582), is essential for ribosomal protein L5 nuclear export (PMID:16648475), and stores/protects ribosomal protein S9 in nucleoli (PMID:18420587). This is a core function. Reason: Ribosome biogenesis is one of the most well-established core functions of NPM1. Supporting Evidence: PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome. PMID:16648475 Nucleophosmin is essential for ribosomal protein L5 nuclear export.
GO:0042274 ribosomal small subunit biogenesis	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 binds the small ribosomal subunit (PMID:18809582) and interacts with ribosomal protein S9 to facilitate its nucleolar storage and ribosome biogenesis (PMID:18420587). The IBA annotation is phylogenetically supported. Reason: NPM1 is involved in both large and small ribosomal subunit biogenesis through its chaperone and export functions. Supporting Evidence: PMID:18420587 Our results suggest that B23 selectively stores, and protects ribosomal protein S9 in nucleoli and therefore could facilitate ribosome biogenesis.
GO:0045944 positive regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: NPM1 acts as a transcription coactivator. It enhances acetylation-dependent chromatin transcription (PMID:16107701), acts as an NF-kappaB coactivator for SOD2 induction (PMID:15087454), and in complex with MYC enhances MYC target gene transcription (PMID:25956029). However, NPM1 can also act as a transcriptional corepressor with AP2alpha (PMID:17318229). The positive regulation annotation is appropriate but represents a non-core pleiotropic function rather than a core molecular activity. Reason: Transcriptional coactivation is a documented activity of NPM1 but is secondary to its core histone chaperone and ribosome biogenesis functions.
GO:1990904 ribonucleoprotein complex	IBA GO_REF:0000033	ACCEPT	Summary: NPM1 is associated with ribonucleoprotein complexes, consistent with its role in ribosome biogenesis and its binding to ribosomal subunits (PMID:18809582). IDA evidence from PMID:18809582 supports this localization. Reason: NPM1 is a component of ribonucleoprotein complexes as part of its core role in ribosome biogenesis.
GO:0003676 nucleic acid binding	IEA GO_REF:0000120	ACCEPT	Summary: NPM1 binds both RNA (rRNA, mRNA) and DNA. This IEA annotation to nucleic acid binding is a parent of the more specific RNA binding (GO:0003723) already accepted via IBA. While correct, it is redundant with more specific annotations. Reason: NPM1 binds nucleic acids broadly. The IEA is consistent with accepted IBA for RNA binding. Acceptable as a broader IEA even though more specific terms exist.
GO:0003723 RNA binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation duplicating the IBA for RNA binding already accepted. NPM1 RNA binding is well-established experimentally (PMID:24106084, PMID:12058066). Reason: Consistent with IBA and IDA evidence for RNA binding. Redundant but not incorrect.
GO:0005654 nucleoplasm	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for nucleoplasm. NPM1 translocates to the nucleoplasm under stress or serum starvation. Consistent with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is well-established for NPM1. Redundant with IBA but correct.
GO:0005730 nucleolus	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for nucleolus. NPM1 is one of the most abundant nucleolar proteins. Redundant with IBA and many IDA annotations. Reason: Nucleolus is the primary localization of NPM1. Correct and consistent.
GO:0005813 centrosome	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for centrosome. NPM1 associates with unduplicated centrosomes (PMID:11051553). Consistent with IBA and IDA annotations. Reason: Centrosome localization is well-established. Redundant but correct.
GO:0010604 positive regulation of macromolecule metabolic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Very broad IEA annotation. NPM1 does positively regulate macromolecule metabolism through its roles in ribosome biogenesis and transcription coactivation. However, this term is too general to be informative. Reason: While technically correct, this is an extremely broad term that adds no informative value beyond what is captured by more specific annotations for ribosome biogenesis and transcription regulation.
GO:0042127 regulation of cell population proliferation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: NPM1 regulates cell proliferation through multiple mechanisms including ribosome biogenesis, centrosome duplication, p53 regulation, and ATF5 degradation (PMID:22528486, PMID:12080348). This is a pleiotropic downstream consequence. Reason: Cell proliferation regulation is an indirect consequence of NPM1 core functions (ribosome biogenesis, centrosome duplication, p53/ARF regulation). Not a core molecular function but is well-supported.
GO:0042254 ribosome biogenesis	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for ribosome biogenesis. NPM1 is central to ribosome biogenesis through rRNA processing, ribosomal protein chaperoning, and ribosomal subunit export (PMID:18809582, PMID:16648475, PMID:18420587). Consistent with IBA annotations for large and small subunit biogenesis. Reason: Ribosome biogenesis is a core function of NPM1. This is a parent term of the more specific subunit biogenesis terms already accepted.
GO:0043066 negative regulation of apoptotic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: IEA annotation for negative regulation of apoptosis. NPM1 inhibits apoptosis through PKR inhibition (PMID:12882984) and p53 regulation. This is a pleiotropic downstream effect. Reason: Anti-apoptotic activity is a secondary consequence of NPM1 core functions, particularly PKR inhibition. Well-supported but not a core molecular activity.
GO:0005515 protein binding	IPI PMID:15144954 Nucleolar protein NPM interacts with HDM2 and protects tumor...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:15144954 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:15161933 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:15989956 ARF-BP1/Mule is a critical mediator of the ARF tumor suppres...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:15989956 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:16376884 Characterisation of the interface between nucleophosmin (NPM...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:16376884 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:16540653 Delocalization and destabilization of the Arf tumor suppress...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:16540653 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:16957780 Antiviral action of the tumor suppressor ARF.	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:16957780 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:17318229 Nucleophosmin acts as a novel AP2alpha-binding transcription...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:17318229 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:17353931 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:17602943 Physical and functional interaction between a nucleolar prot...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:17602943 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:18243139 The nucleocapsid protein of SARS-associated coronavirus inhi...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:18243139 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:18259216 The nucleolar SUMO-specific protease SENP3 reverses SUMO mod...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:18259216 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:20618440 Proteomic and biochemical analysis of 14-3-3-binding protein...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:20618440 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:20701745 Karyopherin alpha7 (KPNA7), a divergent member of the import...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:20701745 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:21326211 The SUMO system controls nucleolar partitioning of a novel m...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:21326211 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:21822216 Nucleophosmin deposition during mRNA 3' end processing influ...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:21822216 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:21988832 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:22510990 AKT-dependent phosphorylation of Niban regulates nucleophosm...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:22510990 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:22712502 Erythroid differentiation-associated gene interacts with NPM...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:22712502 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:23816991 Exploration of binary virus-host interactions using an infec...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:23816991 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:23892143 Human respiratory syncytial virus N, P and M protein interac...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:23892143 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:24462683 Interaction between nucleophosmin and HBV core protein incre...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:24462683 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:24857377 Phosphorylation of multifunctional nucleolar protein nucleop...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:24857377 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:25416956 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:26496610 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:28255170 Nucleophosmin Interacts with PIN2/TERF1-interacting Telomera...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:28255170 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:28611246 Inhibition of Avian Influenza A Virus Replication in Human C...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:28611246 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:29568061 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:30021884 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:31515488 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:32296183 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:32814053 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:33961781 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:35271311 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:35709258 Spatial centrosome proteome of human neural cells uncovers d...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:35709258 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:38029384 Proteomics analysis identifies the ribosome associated coile...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:38029384 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:39251607 Systematic identification of post-transcriptional regulatory...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:39251607 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0001652 granular component	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for granular component of the nucleolus. NPM1 co-localizes with methylated RPS10 in the GC region (UniProt). The GC is where pre-ribosomal particles mature, consistent with NPM1 ribosome biogenesis role. Reason: NPM1 is well-documented to localize in the granular component of the nucleolus where pre-ribosomal particles are assembled. Consistent with core function.
GO:0005634 nucleus	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for nucleus. NPM1 is primarily a nuclear protein (nucleolar). This is a very broad term but consistent with multiple IDA annotations. Reason: NPM1 is a nuclear protein. Correct and consistent, though very broad.
GO:0005737 cytoplasm	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for cytoplasm. NPM1 shuttles to the cytoplasm as part of ribosome export function (PMID:9121481). Consistent with IBA annotation. Reason: Cytoplasmic localization is consistent with NPM1 nucleocytoplasmic shuttling. Redundant with IBA but correct.
GO:0005829 cytosol	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for cytosol. NPM1 can be found in the cytosol as part of its shuttling function and in the NPM1-ALK fusion context. Reason: Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling. More specific than cytoplasm.
GO:0015934 large ribosomal subunit	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for large ribosomal subunit localization. NPM1 directly binds the large ribosomal subunit as part of its nuclear export chaperone function (PMID:18809582, PMID:16648475). Reason: NPM1 associates with maturing 60S ribosomal subunits. Consistent with its ribosome export chaperone function.
GO:0015935 small ribosomal subunit	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for small ribosomal subunit localization. NPM1 binds both large and small ribosomal subunits (PMID:18809582). Reason: NPM1 binds small ribosomal subunits. Consistent with its rate-limiting ribosome export chaperone role.
GO:0016607 nuclear speck	IEA GO_REF:0000107	UNDECIDED	Summary: IEA annotation for nuclear speck localization. While NPM1 is primarily nucleolar, some evidence suggests it may transiently associate with nuclear speckles. However, this is not well-established as a core localization. Reason: Nuclear speck localization for NPM1 is not well-characterized in the primary literature. The IEA transfer may be based on weak or indirect evidence. Unable to confirm without access to the original ortholog data.
GO:0019843 rRNA binding	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for rRNA binding. NPM1 binds rRNA through its C-terminal domain and intrinsically disordered basic region (PMID:24106084). This is more specific than the accepted RNA binding and directly supports ribosome biogenesis. Reason: rRNA binding is a well-established core function of NPM1. More specific than the accepted RNA binding term.
GO:0042802 identical protein binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for identical protein binding. NPM1 forms pentamers and decamers through homooligomerization (PMID:24106084, PMID:9121481). This is confirmed by IDA for protein homodimerization activity. Reason: NPM1 oligomerization is a fundamental property. Consistent with IDA for homodimerization. Oligomerization is essential for NPM1 function.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for positive regulation of transcription by Pol II. Redundant with the IBA and IDA annotations for this term already reviewed. Reason: Transcriptional coactivation is a non-core pleiotropic function of NPM1. Redundant with IBA annotation already reviewed.
GO:1904751 positive regulation of protein localization to nucleolus	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for positive regulation of protein localization to nucleolus. NPM1 mediates nucleolar localization of several proteins including HIV Tat (PMID:9094689), ribosomal proteins (PMID:18420587), and WRN helicase. This is consistent with its chaperoning/shuttling function. Reason: NPM1 acts as a chaperone/shuttle for nucleolar localization of multiple proteins. Well-supported by multiple studies.
GO:0004860 protein kinase inhibitor activity	IDA PMID:12882984 Nucleophosmin interacts with and inhibits the catalytic func...	ACCEPT	Summary: NPM1 inhibits PKR (EIF2AK2) autophosphorylation and catalytic function in a dose-dependent manner (PMID:12882984). Overexpression of NPM suppressed PKR activity, enhanced protein synthesis, and inhibited apoptosis. This is a specific molecular function. Reason: PMID:12882984 directly demonstrated that recombinant NPM inhibited PKR activation in kinase assays. This is a genuine enzymatic inhibitor activity. Supporting Evidence: PMID:12882984 Kinase assays demonstrated that recombinant NPM inhibited PKR activation in a dose-dependent manner.
GO:0007249 canonical NF-kappaB signal transduction	IMP PMID:15087454 Identification of nucleophosmin as an NF-kappaB co-activator...	KEEP AS NON CORE	Summary: PMID:15087454 showed NPM1 acts as an NF-kappaB coactivator for SOD2 gene induction. NPM physically interacts with NF-kappaB and increasing NPM expression leads to increased SOD2 transcription. This represents involvement in NF-kappaB signaling. Reason: NF-kappaB signaling involvement is a pleiotropic downstream effect of NPM1 transcription coactivator function. Not a core molecular function. Supporting Evidence: PMID:15087454 Co-immunoprecipitation studies suggest a physical interaction between NPM and NF-kappaB proteins.
GO:2000767 positive regulation of cytoplasmic translation	IDA PMID:12882984 Nucleophosmin interacts with and inhibits the catalytic func...	KEEP AS NON CORE	Summary: PMID:12882984 showed that overexpression of NPM enhanced protein synthesis by inhibiting PKR, which normally phosphorylates eIF2alpha to suppress translation. This is an indirect effect mediated through PKR inhibition. Reason: Enhanced translation is a downstream consequence of PKR inhibition by NPM1, not a direct translational regulation activity. Supporting Evidence: PMID:12882984 Overexpression of NPM suppressed PKR activity, enhanced protein synthesis, and inhibited apoptosis.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation based on immunofluorescence data curation (GO_REF:0000052). NPM1 is found in the nucleoplasm under stress or specific conditions. Consistent with IBA and other IDA annotations. Reason: Nucleoplasm localization is well-established for NPM1 across multiple evidence types.
GO:0005730 nucleolus	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation based on immunofluorescence data curation. NPM1 is one of the most abundant nucleolar proteins. Consistent with IBA and many other IDA annotations. Reason: Nucleolus is the primary localization of NPM1. Well-established across many studies.
GO:0005634 nucleus	IDA PMID:38231884 ARID3C Acts as a Regulator of Monocyte-to-Macrophage Differe...	ACCEPT	Summary: IDA annotation for nucleus from PMID:38231884 which studied ARID3C-NPM1 interaction. NPM1 was shown to shuttle between cytoplasm and nucleus, mediating ARID3C nuclear import. Reason: Nuclear localization of NPM1 is well-established. PMID:38231884 confirmed NPM1 is nuclear.
GO:0006606 protein import into nucleus	IDA PMID:38231884 ARID3C Acts as a Regulator of Monocyte-to-Macrophage Differe...	KEEP AS NON CORE	Summary: PMID:38231884 demonstrated that NPM1 mediates ARID3C nuclear shuttling. ARID3C forms a complex with NPM1 to translocate to the nucleus. When the ARID3C-NPM1 binding site was mutated, ARID3C was retained in the cytoplasm. Reason: NPM1 acts as a nuclear import adaptor for ARID3C. This is consistent with NPM1 general protein chaperoning function but is a specific case, not a core function. Supporting Evidence: PMID:38231884 ARID3C forms a complex with NPM1 to translocate to the nucleus, acting as a transcription factor that promotes the expression of the genes involved in monocyte-to-macrophage differentiation.
GO:0030225 macrophage differentiation	IDA PMID:38231884 ARID3C Acts as a Regulator of Monocyte-to-Macrophage Differe...	MARK AS OVER ANNOTATED	Summary: PMID:38231884 showed ARID3C-NPM1 complex promotes monocyte-to-macrophage differentiation. NPM1 role is as an adaptor for ARID3C nuclear import, not a direct driver of macrophage differentiation. Reason: NPM1 is an adaptor for ARID3C nuclear import. The macrophage differentiation activity is primarily driven by ARID3C as transcription factor, not by NPM1 directly. This annotation over-attributes the differentiation process to NPM1. Supporting Evidence: PMID:38231884 ARID3C was found to predominantly localize with the nucleus, where it functioned as a transcription factor for genes STAT3, STAT1, and JUNB, thereby facilitating monocyte-to-macrophage differentiation.
GO:0060090 molecular adaptor activity	IDA PMID:38231884 ARID3C Acts as a Regulator of Monocyte-to-Macrophage Differe...	ACCEPT	Summary: PMID:38231884 demonstrated NPM1 acts as an adaptor for ARID3C nuclear shuttling. NPM1 brings ARID3C to the nucleus through selective binding. This represents a genuine adaptor function. Reason: NPM1 acts as a molecular adaptor for ARID3C nuclear import. This is consistent with NPM1 broader role as a nucleocytoplasmic shuttling chaperone for multiple cargo proteins. Supporting Evidence: PMID:38231884 Mutating this binding site prevented ARID3C from interacting with NPM1, resulting in its retention in the cytoplasm instead of translocation to the nucleus.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9725009	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-9725009). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9725023	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-9725023). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9725030	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-9725030). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9851090	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-9851090). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005829 cytosol	TAS Reactome:R-HSA-9700181	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700181). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9700190	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700190). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9700193	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700193). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9710914	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9710914). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9710917	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9710917). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712078	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712078). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712079	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712079). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712081	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712081). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712082	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712082). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712083	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712083). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712084	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712084). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712085	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712085). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712086	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712086). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712087	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712087). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9712088	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712088). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9724099	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9724099). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9725009	ACCEPT	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9725009). NPM1 shuttles to the cytoplasm/cytosol as part of its normal function in ribosome export and protein transport. Reason: Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling function.
GO:0005829 cytosol	TAS Reactome:R-HSA-9850958	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9850958). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0019843 rRNA binding	IPI PMID:24106084 Intrinsically disordered regions of nucleophosmin/B23 regula...	ACCEPT	Summary: PMID:24106084 demonstrated that NPM1/B23 RNA binding activity is essential for ribosome biogenesis, with the C-terminal domain and intrinsically disordered basic region mediating RNA binding. The basic IDR alone strongly binds to RNA. Reason: rRNA binding is a core molecular function of NPM1. Directly demonstrated in PMID:24106084. Supporting Evidence: PMID:24106084 Nucleophosmin (NPM1/B23) is a nucleolar protein implicated in growth-associated functions, in which the RNA binding activity of B23 plays essential roles in ribosome biogenesis.
GO:0042803 protein homodimerization activity	IPI PMID:24106084 Intrinsically disordered regions of nucleophosmin/B23 regula...	ACCEPT	Summary: PMID:24106084 showed NPM1 forms homo-oligomers (pentamers/decamers) through inter-molecular interactions of its IDRs. The N-terminal domain mediates oligomerization. Reason: NPM1 forms pentamers and decamers through homooligomerization. This is a fundamental property confirmed by crystal structure (PDB:2P1B) and multiple biochemical studies. Supporting Evidence: PMID:24106084 Chemical cross-linking experiments and fluorescent labeling of bipartite tetracysteine-tagged proteins suggested that the inter- and intra-molecular interactions between the two IDRs contribute to the regulation of the RNA binding activity of CTD to control the cellular localization and functions of B23.
GO:0005515 protein binding	IPI PMID:23972994 ABH2 couples regulation of ribosomal DNA transcription with ...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:23972994 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0090398 cellular senescence	IMP PMID:12080348 Nucleophosmin regulates the stability and transcriptional ac...	KEEP AS NON CORE	Summary: PMID:12080348 showed NPM1 regulates p53 stability and transcriptional activity. NPM1 overexpression suppressed cell growth. The connection to senescence is through p53 regulation. Reason: Cellular senescence is a downstream phenotypic consequence of NPM1 effects on p53 stabilization. Not a core molecular function but a pleiotropic effect.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4086088	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-4086088). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4086059	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-4086059). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005515 protein binding	IPI PMID:25956029 The Nucleolar Protein GLTSCR2 Is an Upstream Negative Regula...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:25956029 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005829 cytosol	TAS Reactome:R-HSA-9700131	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700131). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:0005829 cytosol	TAS Reactome:R-HSA-9700179	KEEP AS NON CORE	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700179). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function. Reason: Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
GO:1990904 ribonucleoprotein complex	IDA PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chape...	ACCEPT	Summary: IDA annotation from PMID:18809582 which demonstrated NPM1 serves as a rate-limiting nuclear export chaperone for the mammalian ribosome. NPM1 was found associated with ribonucleoprotein complexes. Reason: NPM1 associates with ribonucleoprotein complexes as part of its core ribosome biogenesis and export function. Directly demonstrated. Supporting Evidence: PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
GO:0005730 nucleolus	IDA PMID:19208757 Nucleolar structure and function are regulated by the deubiq...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:19208757. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:1902629 regulation of mRNA stability involved in cellular response to UV	IMP PMID:12080348 Nucleophosmin regulates the stability and transcriptional ac...	UNDECIDED	Summary: PMID:12080348 primarily demonstrated NPM1 regulation of p53 stability and transcriptional activity. The connection to mRNA stability in UV response seems tenuous for this reference. Reason: The specific mechanism by which NPM1 regulates mRNA stability in UV response is not clearly demonstrated in PMID:12080348. Need to verify this annotation against the primary data.
GO:0001652 granular component	TAS Reactome:R-HSA-9727886	ACCEPT	Summary: TAS annotation for granular component from Reactome (SARS-CoV-1 N protein binds NPM1). NPM1 localizes to the GC of the nucleolus. This Reactome entry is about viral interaction but the localization is correct. Reason: NPM1 localizes to the granular component of the nucleolus. Correct localization, consistent with IEA annotation and UniProt.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-180728	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-180728). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-180736	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-180736). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-606287	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-606287). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-606289	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-606289). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-606326	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-606326). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8869542	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-8869542). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8869543	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-8869543). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8869549	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-8869549). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8869568	ACCEPT	Summary: TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-8869568). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations. Reason: Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
GO:0005730 nucleolus	IDA PMID:25956029 The Nucleolar Protein GLTSCR2 Is an Upstream Negative Regula...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:25956029. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:25956029 The Nucleolar Protein GLTSCR2 Is an Upstream Negative Regula...	KEEP AS NON CORE	Summary: PMID:25956029 showed NPM1 in complex with MYC enhances transcription of MYC target genes. NOP53 acts as upstream negative regulator by competing with MYC for NPM1 binding. Reason: Transcription coactivation is a non-core pleiotropic function. Redundant with IBA annotation. Supporting Evidence: PMID:25956029 The nucleolar protein GLTSCR2 is an upstream negative regulator of the oncogenic Nucleophosmin-MYC axis.
GO:0001046 core promoter sequence-specific DNA binding	IDA PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	UNDECIDED	Summary: PMID:19160485 studied the L23-NPM1-Miz1 circuit. NPM1 was shown to be present at core promoters in complex with Miz1. However, NPM1 DNA binding may be indirect through the complex. Reason: NPM1 is primarily known as a histone/RNA chaperone, not a DNA-binding protein per se. Its presence at promoters may be through protein complexes rather than direct DNA sequence-specific binding. Need more evidence to confirm direct DNA binding.
GO:0003713 transcription coactivator activity	IDA PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	KEEP AS NON CORE	Summary: PMID:19160485 showed NPM1 coordinates Miz1 function with cell growth through the L23-NPM1-Miz1 circuit. NPM1 acts as a coactivator in this context. Reason: Transcription coactivator activity is a non-core function of NPM1. It is documented but secondary to histone chaperoning and ribosome biogenesis.
GO:0005515 protein binding	IPI PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:19160485 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005654 nucleoplasm	IDA PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	ACCEPT	Summary: IDA annotation for nucleoplasm from PMID:19160485, which studied the ribosomal protein L23-NPM1 circuit coordinating Miz1 function with cell growth. NPM1 was shown in the nucleoplasm in this context. Reason: Nucleoplasm localization is well-established for NPM1. Consistent with multiple other evidence.
GO:0005730 nucleolus	IDA PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:19160485. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:0032991 protein-containing complex	IDA PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	ACCEPT	Summary: IDA annotation for protein-containing complex from PMID:19160485. NPM1 forms complexes with many proteins including the L23-Miz1 complex. Reason: NPM1 exists in multiple protein complexes (pentamer/decamer, ribosomal complexes, transcription complexes). This is a general but correct localization term.
GO:0032993 protein-DNA complex	IDA PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	KEEP AS NON CORE	Summary: IDA annotation for protein-DNA complex. PMID:19160485 showed NPM1 is found in protein-DNA complexes at promoters in the L23-Miz1 circuit. Reason: NPM1 association with protein-DNA complexes is context-dependent and related to its transcription coactivator function, not a core activity.
GO:0034644 cellular response to UV	IDA PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	KEEP AS NON CORE	Summary: PMID:19160485 showed NPM1 role in cellular response to UV through the L23-NPM1-Miz1 pathway. Under UV stress, ribosomal stress releases L23 which disrupts NPM1-Miz1 complex. Reason: UV response involvement is a stress-related function secondary to NPM1 core roles. NPM1 translocates from nucleolus under stress conditions.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	KEEP AS NON CORE	Summary: IDA annotation for positive regulation of transcription from PMID:19160485 studying L23-NPM1-Miz1 circuit. Redundant with other transcription coactivation annotations. Reason: Transcription coactivation is a non-core function. Redundant with IBA annotation already reviewed.
GO:0140297 DNA-binding transcription factor binding	IPI PMID:19160485 A ribosomal protein L23-nucleophosmin circuit coordinates Mi...	ACCEPT	Summary: PMID:19160485 showed NPM1 interacts with Miz1 transcription factor. NPM1 also interacts with AP2alpha (PMID:17318229), NF-kappaB (PMID:15087454), and MYC (PMID:25956029). Reason: NPM1 binds multiple transcription factors as part of its coactivator/corepressor function. This is more specific than protein binding and captures a real molecular function. Supporting Evidence: PMID:17318229 Nucleophosmin (NPM) is an important nucleolar phosphoprotein with pleiotropic functions in various cellular processes.
GO:0005829 cytosol	TAS Reactome:R-HSA-6801675	ACCEPT	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-6801675). NPM1 shuttles to the cytoplasm/cytosol as part of its normal function in ribosome export and protein transport. Reason: Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling function.
GO:0005515 protein binding	IPI PMID:23019224 DDX31 regulates the p53-HDM2 pathway and rRNA gene transcrip...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:23019224 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:22528486 Nucleophosmin (NPM1/B23) interacts with activating transcrip...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:22528486 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005730 nucleolus	IDA PMID:22528486 Nucleophosmin (NPM1/B23) interacts with activating transcrip...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:22528486. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:0008284 positive regulation of cell population proliferation	IDA PMID:22528486 Nucleophosmin (NPM1/B23) interacts with activating transcrip...	KEEP AS NON CORE	Summary: PMID:22528486 showed NPM1 antagonizes ATF5 inhibitory effect on cell proliferation and promotes ATF5 degradation in hepatocellular carcinoma cells. Reason: Cell proliferation promotion through ATF5 degradation is a context-specific pleiotropic effect, not a core molecular function. Supporting Evidence: PMID:22528486 NPM1-promoted ATF5 down-regulation diminished ATF5-mediated repression of cAMP-responsive element-dependent gene transcription and abrogates ATF5-induced G(2)/M cell cycle blockade and inhibition of cell proliferation in HCC cells.
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:22528486 Nucleophosmin (NPM1/B23) interacts with activating transcrip...	KEEP AS NON CORE	Summary: PMID:22528486 showed NPM1 promotes ATF5 degradation, relieving ATF5-mediated transcriptional repression. This is an indirect transcription regulation effect. Reason: Positive transcription regulation through ATF5 degradation is indirect. Not a core function.
GO:1902751 positive regulation of cell cycle G2/M phase transition	IDA PMID:22528486 Nucleophosmin (NPM1/B23) interacts with activating transcrip...	KEEP AS NON CORE	Summary: PMID:22528486 showed NPM1 relieves ATF5-induced G2/M blockade through ATF5 degradation. Reason: G2/M transition regulation is an indirect consequence of ATF5 degradation by NPM1. Not a core function. Supporting Evidence: PMID:22528486 NPM1 interaction with ATF5 displaces HSP70, a known ATF5-interacting protein, from ATF5 protein complexes and antagonizes its role in stabilization of ATF5 protein.
GO:0005515 protein binding	IPI PMID:20075868 Nucleolar retention of a translational C/EBPalpha isoform st...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:20075868 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005925 focal adhesion	HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome...	REMOVE	Summary: HDA annotation for focal adhesion from a high-throughput proteomics study of myosin-II-responsive focal adhesion proteome. NPM1 is primarily nucleolar, not known to have focal adhesion functions. Reason: Focal adhesion localization is likely an artifact of the high-throughput proteomics approach. NPM1 is a nucleolar protein with no established role in focal adhesions.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	REMOVE	Summary: HDA annotation for membrane from a high-throughput study defining the membrane proteome of NK cells. NPM1 is not a membrane protein. Reason: Membrane localization is likely a contaminant in the high-throughput proteomics screen. NPM1 is a nucleolar/nuclear protein with no transmembrane domain or membrane association.
GO:0005515 protein binding	IPI PMID:22720776 PHF6 interacts with the nucleosome remodeling and deacetylat...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:22720776 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005634 nucleus	IDA PMID:22720776 PHF6 interacts with the nucleosome remodeling and deacetylat...	ACCEPT	Summary: IDA annotation for nucleus from PMID:22720776 (PHF6 interacts with NuRD complex). NPM1 is well-established as a nuclear protein. Reason: Nuclear localization is fundamental to NPM1. Consistent with all other evidence.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	ACCEPT	Summary: HDA annotation for nucleus from PMID:21630459 (proteomic characterization of human sperm nucleus). NPM1 is a nuclear protein. Reason: Nuclear localization is correct for NPM1. Consistent with all other evidence.
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	ACCEPT	Summary: HDA annotation for RNA binding from PMID:22658674 (atlas of mammalian mRNA-binding proteins). NPM1 binds RNA including mRNA and rRNA. Reason: RNA binding is a core function of NPM1. Consistent with IBA and IDA evidence. Supporting Evidence: PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
GO:0003723 RNA binding	HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ...	ACCEPT	Summary: HDA annotation for RNA binding from PMID:22681889 (mRNA-bound proteome study). NPM1 was identified as an mRNA-binding protein. Reason: RNA binding is a core function of NPM1. Consistent with extensive evidence.
GO:0005515 protein binding	IPI PMID:12882984 Nucleophosmin interacts with and inhibits the catalytic func...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:12882984 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0043066 negative regulation of apoptotic process	IDA PMID:12882984 Nucleophosmin interacts with and inhibits the catalytic func...	KEEP AS NON CORE	Summary: PMID:12882984 showed NPM1 overexpression inhibited apoptosis through PKR inhibition. Enforced NPM expression in FA lymphoblasts reduced aberrant apoptotic responses. Reason: Anti-apoptotic function through PKR inhibition is well-demonstrated but is a secondary pleiotropic effect, not a core molecular function. Supporting Evidence: PMID:12882984 Overexpression of NPM suppressed PKR activity, enhanced protein synthesis, and inhibited apoptosis.
GO:0005829 cytosol	TAS Reactome:R-HSA-180725	ACCEPT	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-180725). NPM1 shuttles to the cytoplasm/cytosol as part of its normal function in ribosome export and protein transport. Reason: Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling function.
GO:0005829 cytosol	TAS Reactome:R-HSA-9835328	ACCEPT	Summary: TAS annotation for cytosol from Reactome (Reactome:R-HSA-9835328). NPM1 shuttles to the cytoplasm/cytosol as part of its normal function in ribosome export and protein transport. Reason: Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling function.
GO:0019901 protein kinase binding	IPI PMID:20352051 Polo-like kinase 2-dependent phosphorylation of NPM/B23 on s...	ACCEPT	Summary: PMID:20352051 showed NPM1 directly interacts with PLK2 in a Polo-box dependent manner. PLK2 phosphorylates NPM1 at Ser4 to trigger centriole duplication. Reason: NPM1 binds protein kinases PLK2, CDK2/cyclin E, ROCK2, and Aurora kinases as part of its regulatory roles. More specific than protein binding. Supporting Evidence: PMID:20352051 We find that Plk2 and NPM/B23 interact in vitro in a Polo-box dependent manner. An association between both proteins was also observed in vivo.
GO:0046599 regulation of centriole replication	IMP PMID:20352051 Polo-like kinase 2-dependent phosphorylation of NPM/B23 on s...	ACCEPT	Summary: PMID:20352051 demonstrated PLK2 phosphorylation of NPM1 at Ser4 triggers centriole duplication. Non-phosphorylatable S4A mutant interfered with centriole reduplication. Reason: Regulation of centriole replication is a core function of NPM1, demonstrated through phospho-mutant analysis. Supporting Evidence: PMID:20352051 Notably, expression of a non-phosphorylatable NPM/B23 S4A mutant interferes with centriole reduplication in S-phase arrested cells and leads to a dilution of centriole numbers in unperturbed U2OS cells.
GO:0005515 protein binding	IPI PMID:17015463 Interaction between ROCK II and nucleophosmin/B23 in the reg...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:17015463 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005730 nucleolus	IDA PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chape...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:18809582. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:0006281 DNA repair	IDA PMID:19188445 APE1/Ref-1 interacts with NPM1 within nucleoli and plays a r...	KEEP AS NON CORE	Summary: PMID:19188445 showed NPM1 interacts with APEX1/Ref-1 in nucleoli and plays a role in rRNA quality control. NPM1 stimulates APEX1 endonuclease activity on AP double-stranded DNA. This represents a role in DNA repair within the rDNA context. Reason: DNA repair involvement is secondary to NPM1 core nucleolar function. The role is specifically in rRNA quality control through APEX1 regulation. Supporting Evidence: PMID:19188445 APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in the rRNA quality control process.
GO:0005515 protein binding	IPI PMID:19188445 APE1/Ref-1 interacts with NPM1 within nucleoli and plays a r...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:19188445 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005730 nucleolus	IDA PMID:19188445 APE1/Ref-1 interacts with NPM1 within nucleoli and plays a r...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:19188445. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:0005515 protein binding	IPI PMID:20159986 Methylation of ribosomal protein S10 by protein-arginine met...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:20159986 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005515 protein binding	IPI PMID:19410545 HJURP is a cell-cycle-dependent maintenance and deposition f...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:19410545 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0043023 ribosomal large subunit binding	IDA PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chape...	ACCEPT	Summary: PMID:18809582 directly demonstrated NPM1 binds the large ribosomal subunit as part of its rate-limiting nuclear export chaperone function. Reason: Large ribosomal subunit binding is a core molecular function of NPM1. Directly demonstrated. Supporting Evidence: PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
GO:0043024 ribosomal small subunit binding	IDA PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chape...	ACCEPT	Summary: PMID:18809582 demonstrated NPM1 binds both large and small ribosomal subunits. Reason: Small ribosomal subunit binding is a core molecular function of NPM1. Directly demonstrated. Supporting Evidence: PMID:18809582 Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
GO:0010826 negative regulation of centrosome duplication	IMP PMID:16041368 Temporal and spatial control of nucleophosmin by the Ran-Crm...	ACCEPT	Summary: PMID:16041368 showed Ran-Crm1 controls NPM1 association with centrosomes. NPM1 acts as a negative regulator - its presence on unduplicated centrosomes prevents duplication until it is phosphorylated and released. Reason: Negative regulation of centrosome duplication is a core function of NPM1. NPM1 licensing of centrosome duplication through its phosphorylation-dependent dissociation.
GO:0003723 RNA binding	IDA PMID:12058066 The RNA binding activity of a ribosome biogenesis factor, nu...	ACCEPT	Summary: IDA annotation for RNA binding from PMID:12058066 which showed RNA binding activity of B23 is modulated by phosphorylation with cell cycle-dependent kinase. Reason: RNA binding is a core function of NPM1. Directly demonstrated by IDA. Supporting Evidence: PMID:12058066 It has been shown that B23 binds to nucleic acids, digests RNA, and is localized in nucleolar granular components from which preribosomal particles are transported to cytoplasm.
GO:0005654 nucleoplasm	IDA PMID:12058066 The RNA binding activity of a ribosome biogenesis factor, nu...	ACCEPT	Summary: IDA annotation for nucleoplasm from PMID:12058066. NPM1 is found in the nucleoplasm particularly when phosphorylated. Consistent with other evidence. Reason: Nucleoplasm localization is well-established. Consistent with other evidence.
GO:0005730 nucleolus	IDA PMID:16041368 Temporal and spatial control of nucleophosmin by the Ran-Crm...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:16041368. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:0006913 nucleocytoplasmic transport	IDA PMID:16041368 Temporal and spatial control of nucleophosmin by the Ran-Crm...	ACCEPT	Summary: IDA annotation for nucleocytoplasmic transport from PMID:16041368 showing Ran-Crm1 controls NPM1 shuttling for centrosome duplication regulation. Reason: Nucleocytoplasmic transport is a core function of NPM1, regulated by Ran-Crm1 pathway.
GO:0007165 signal transduction	NAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied...	MARK AS OVER ANNOTATED	Summary: NAS annotation for signal transduction from PMID:16130169 (proteomics of etoposide-induced apoptosis in endothelial cells). Very broad term. NPM1 has indirect roles in signaling through p53, ARF, and PKR pathways. Reason: Signal transduction is far too broad for NPM1. Its signaling roles are indirect, through specific pathways (p53, PKR inhibition). The NAS evidence from a proteomics study is weak.
GO:0031616 spindle pole centrosome	IDA PMID:16041368 Temporal and spatial control of nucleophosmin by the Ran-Crm...	ACCEPT	Summary: IDA annotation for spindle pole centrosome from PMID:16041368 which showed NPM1 associates with centrosomes during mitosis, controlled by Ran-Crm1. Reason: NPM1 localizes to spindle pole centrosomes during mitosis. Consistent with its centrosome cycle regulation function.
GO:0043066 negative regulation of apoptotic process	NAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied...	KEEP AS NON CORE	Summary: NAS annotation for negative regulation of apoptosis from PMID:16130169 (proteomics study). NPM1 anti-apoptotic activity is better supported by PMID:12882984 (PKR inhibition). Reason: Anti-apoptotic function is a secondary pleiotropic effect. Better supported by other evidence. NAS from proteomics is weak but the function is real.
GO:0005515 protein binding	IPI PMID:16648475 Nucleophosmin is essential for ribosomal protein L5 nuclear ...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:16648475 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0006334 nucleosome assembly	IDA PMID:11602260 Function of nucleophosmin/B23, a nucleolar acidic protein, a...	ACCEPT	Summary: PMID:11602260 directly demonstrated NPM1 mediates nucleosome assembly and decondenses sperm chromatin. This is a histone chaperone function. Reason: Nucleosome assembly is a core function of NPM1 as a histone chaperone. Directly demonstrated. Supporting Evidence: PMID:11602260 Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to mediate formation of nucleosome, and to decondense sperm chromatin.
GO:0042393 histone binding	IDA PMID:11602260 Function of nucleophosmin/B23, a nucleolar acidic protein, a...	ACCEPT	Summary: IDA annotation for histone binding from PMID:11602260. NPM1 binds core histones H3, H2B, and H4. Consistent with IBA annotation already accepted. Reason: Histone binding is a core molecular function of NPM1. Directly demonstrated. Supporting Evidence: PMID:11602260 Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to mediate formation of nucleosome, and to decondense sperm chromatin.
GO:0005515 protein binding	IPI PMID:18420587 Ribosomal protein S9 is a novel B23/NPM-binding protein requ...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:18420587 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0008104 intracellular protein localization	IDA PMID:18420587 Ribosomal protein S9 is a novel B23/NPM-binding protein requ...	ACCEPT	Summary: PMID:18420587 showed NPM1 selectively stores and protects ribosomal protein S9 in nucleoli, facilitating ribosome biogenesis. Reason: NPM1 controls intracellular localization of ribosomal proteins and other cargo. This is part of its core chaperoning function. Supporting Evidence: PMID:18420587 Our results suggest that B23 selectively stores, and protects ribosomal protein S9 in nucleoli and therefore could facilitate ribosome biogenesis.
GO:0005515 protein binding	IPI PMID:17475909 The human Shwachman-Diamond syndrome protein, SBDS, associat...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:17475909 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005730 nucleolus	IDA PMID:17475909 The human Shwachman-Diamond syndrome protein, SBDS, associat...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:17475909. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:0005515 protein binding	IPI PMID:17438371 Detection and identification of transcription factors as int...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:17438371 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005730 nucleolus	IDA PMID:11420665 Diverged nuclear localization of Werner helicase in human an...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:11420665. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:0005515 protein binding	IPI PMID:15184379 Nucleophosmin/B23 is a candidate substrate for the BRCA1-BAR...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:15184379 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0030957 Tat protein binding	IDA PMID:9094689 Protein B23 is an important human factor for the nucleolar l...	KEEP AS NON CORE	Summary: PMID:9094689 showed NPM1/B23 binds HIV Tat protein and is necessary for its nucleolar localization. This is a host-virus interaction. Reason: HIV Tat binding is a specific host-virus interaction, not a core function of NPM1. However, it reflects NPM1 general role as a nucleolar shuttle protein. Supporting Evidence: PMID:9094689 Nucleolar shuttle protein B23 was found to bind to human immunodeficiency virus protein Tat, and this binding required the nucleolar localization motif of Tat.
GO:0051082 unfolded protein binding	IDA PMID:10211837 Nucleolar protein B23 has molecular chaperone activities.	MODIFY	Summary: GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962). The annotation is based on PMID:10211837 (Szebeni & Olson, 1999), which demonstrated that NPM1/B23 has genuine molecular chaperone activities including both holdase (anti-aggregation) and foldase (refolding) functions using multiple protein substrates. B23 inhibited aggregation of HIV-1 Rev protein, protected LADH, carboxypeptidase A, citrate synthase, and rhodanese from thermal aggregation, preserved LADH enzyme activity during heat stress, and promoted restoration of LADH activity after guanidine-HCl denaturation. It preferentially bound denatured substrates and exposed hydrophobic regions when complexed with denatured proteins. The demonstrated refolding activity (foldase function) best maps to GO:0044183 (protein folding chaperone). UniProt also classifies NPM1 with the keyword "Chaperone" and describes it as acting "as a chaperonin for the core histones H3, H2B and H4" (citing PMID:16107701). The histone chaperone activity is separately supported by PMID:11602260, which showed NPM1 binds histones (preferentially H3), mediates nucleosome formation, and decondenses sperm chromatin, and is better captured by GO:0140713 (histone chaperone activity). Since the evidence in PMID:10211837 specifically demonstrates protein folding chaperone activity (not just binding to unfolded proteins), MODIFY to GO:0044183 is appropriate. Reason: GO:0051082 is scheduled for obsolescence (go-ontology#30962). The obsoletion notice specifies that annotations should be redirected to either GO:0044183 (protein folding chaperone, i.e. foldase) or to a holdase chaperone term. PMID:10211837 demonstrates that NPM1 has both holdase activity (preventing aggregation of multiple substrates) and foldase activity (promoting restoration of LADH activity after guanidine-HCl denaturation). Since GO:0044183 captures the foldase/refolding function and NPM1 clearly promotes refolding, this is the most appropriate replacement. Additionally, the histone chaperone function of NPM1 (PMID:11602260, PMID:16107701) is a distinct activity best captured by GO:0140713, which should be proposed as a NEW annotation. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:10211837 Protein B23 inhibited the aggregation of the Rev protein, with the amount of inhibition proportional to the concentration of B23 added. This activity was saturable with nearly complete inhibition when the molar ratio of B23:Rev was slightly above one. PMID:10211837 Protein B23 also protected liver alcohol dehydrogenase (LADH), carboxypeptidase A, citrate synthase, and rhodanese from aggregation during thermal denaturation and preserved the enzyme activity of LADH under these conditions. PMID:10211837 In addition, protein B23 was able to promote the restoration of activity of LADH previously denatured with guanidine-HCl. PMID:10211837 Protein B23 preferentially bound denatured substrates and exposed hydrophobic regions when complexed with denatured proteins. Thus, by several criteria, protein B23 behaves like a molecular chaperone; these activities may be related to its role in ribosome biogenesis. PMID:11602260 Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to mediate formation of nucleosome, and to decondense sperm chromatin. These activities of B23 were dependent on its acidic regions as other histone chaperones, suggesting that B23/nucleophosmin is a member of histone chaperone proteins.
GO:0051059 NF-kappaB binding	IDA PMID:15087454 Identification of nucleophosmin as an NF-kappaB co-activator...	KEEP AS NON CORE	Summary: PMID:15087454 demonstrated physical interaction between NPM and NF-kappaB using co-immunoprecipitation and NF-kappaB affinity chromatography. NPM was the most abundant protein in the NF-kappaB-bound fraction. Reason: NF-kappaB binding is demonstrated but is part of NPM1 non-core transcription coactivator function. Not a core molecular function. Supporting Evidence: PMID:15087454 Co-immunoprecipitation studies suggest a physical interaction between NPM and NF-kappaB proteins.
GO:0003713 transcription coactivator activity	IDA PMID:15087454 Identification of nucleophosmin as an NF-kappaB co-activator...	KEEP AS NON CORE	Summary: PMID:15087454 showed NPM1 acts as NF-kappaB coactivator for SOD2 induction. Increasing NPM expression increased SOD2 transcription dose-dependently. Reason: Transcription coactivator activity is a non-core function. Redundant with annotation from PMID:19160485. Supporting Evidence: PMID:15087454 The results indicate that an increase NPM expression leads to increased MnSOD gene transcription in a dose-dependent manner.
GO:0005813 centrosome	IDA PMID:11051553 Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome...	ACCEPT	Summary: PMID:11051553 showed NPM1 associates specifically with unduplicated centrosomes and dissociates upon CDK2/cyclin E phosphorylation to initiate centrosome duplication. Reason: Centrosome localization is a core feature of NPM1, directly demonstrated by IDA in a landmark study. Supporting Evidence: PMID:11051553 NPM/B23 associates specifically with unduplicated centrosomes, and NPM/B23 dissociates from centrosomes by CDK2/cyclin E-mediated phosphorylation.
GO:0007098 centrosome cycle	IMP PMID:11051553 Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome...	ACCEPT	Summary: PMID:11051553 demonstrated NPM1 is a CDK2/cyclin E substrate in centrosome duplication. NPM1 phosphorylation triggers centrosome duplication initiation. Reason: Centrosome cycle regulation is a core function of NPM1. Landmark study demonstrating direct involvement. Supporting Evidence: PMID:11051553 We identified nucleophosmin (NPM/B23) as a substrate of CDK2/cyclin E in centrosome duplication.
GO:0005515 protein binding	IPI PMID:12080348 Nucleophosmin regulates the stability and transcriptional ac...	REMOVE	Summary: Protein binding (GO:0005515) is uninformative and does not capture the specific molecular function of the interaction. NPM1 interacts with many proteins as part of its diverse functions. This annotation from PMID:12080348 should be replaced with more specific MF terms. Reason: Per curation guidelines, protein binding is too vague to be informative. More specific molecular function terms (e.g. histone chaperone activity, protein folding chaperone, ribosomal subunit binding) better capture NPM1 activities.
GO:0005634 nucleus	IDA PMID:12080348 Nucleophosmin regulates the stability and transcriptional ac...	ACCEPT	Summary: IDA annotation for nucleus from PMID:12080348 which studied NPM1 regulation of p53. NPM1 is a nuclear protein. Consistent with all other evidence. Reason: Nuclear localization is fundamental to NPM1 function. Well-established.
GO:0005730 nucleolus	IDA PMID:12080348 Nucleophosmin regulates the stability and transcriptional ac...	ACCEPT	Summary: IDA annotation for nucleolus from PMID:12080348. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature. Reason: Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
GO:0005737 cytoplasm	IDA PMID:9121481 Role of the nucleophosmin (NPM) portion of the non-Hodgkin's...	ACCEPT	Summary: IDA annotation for cytoplasm from PMID:9121481 which studied the NPM-ALK fusion oncogene. NPM1 was shown to shuttle between nucleus and cytoplasm. Reason: Cytoplasmic localization confirmed by IDA. NPM1 is a nucleocytoplasmic shuttling protein. Supporting Evidence: PMID:9121481 Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear compartments.
GO:0006886 intracellular protein transport	TAS PMID:12080348 Nucleophosmin regulates the stability and transcriptional ac...	ACCEPT	Summary: TAS annotation for intracellular protein transport. NPM1 functions as a nucleocytoplasmic shuttle for ribosomal subunits and other cargo proteins. PMID:12080348 discusses NPM1 shuttling. Reason: Intracellular protein transport is a core function of NPM1. It acts as a nuclear export chaperone for ribosomes and import adaptor for various proteins.
GO:0006913 nucleocytoplasmic transport	TAS PMID:12080348 Nucleophosmin regulates the stability and transcriptional ac...	ACCEPT	Summary: TAS annotation for nucleocytoplasmic transport from PMID:12080348. NPM1 is a well-established nucleocytoplasmic shuttling protein. Reason: Nucleocytoplasmic transport is a core function of NPM1. It shuttles between nucleus and cytoplasm to export ribosomal subunits.
GO:0008285 negative regulation of cell population proliferation	IMP PMID:12080348 Nucleophosmin regulates the stability and transcriptional ac...	KEEP AS NON CORE	Summary: PMID:12080348 showed NPM1 stabilizes p53 and can suppress cell growth. However, NPM1 also has pro-proliferative roles through ribosome biogenesis and ATF5 degradation. The negative regulation may reflect specific contexts. Reason: NPM1 has context-dependent effects on proliferation. The negative regulation is through p53 stabilization in certain conditions. Not a core defining function.
GO:0042255 ribosome assembly	TAS PMID:12080348 Nucleophosmin regulates the stability and transcriptional ac...	ACCEPT	Summary: TAS annotation for ribosome assembly. NPM1 is essential for ribosome biogenesis including assembly, processing, and export (PMID:18809582, PMID:16648475). Reason: Ribosome assembly is a core function of NPM1. Well-supported by multiple direct studies.
GO:0042803 protein homodimerization activity	IDA PMID:9121481 Role of the nucleophosmin (NPM) portion of the non-Hodgkin's...	ACCEPT	Summary: IDA annotation for protein homodimerization from PMID:9121481. NPM1 forms pentamers and decamers. Consistent with IPI from PMID:24106084 and structural data. Reason: NPM1 oligomerization is a fundamental structural property. Forms pentamers/decamers essential for function.
GO:0140713 histone chaperone activity	IDA PMID:11602260 Function of nucleophosmin/B23, a nucleolar acidic protein, a...	NEW	Summary: NPM1 functions as a histone chaperone for core histones H3, H2B, and H4. PMID:11602260 demonstrated NPM1 binds histones (preferentially H3), mediates nucleosome formation, and decondenses sperm chromatin. These activities depend on its acidic regions, as in other histone chaperones. PMID:16107701 showed NPM1 enhances acetylation-dependent chromatin transcription, disrupting nucleosomal structure. UniProt classifies NPM1 as a chaperonin for core histones. GO:0140713 (histone chaperone activity) is the appropriate specific term for this well-documented function that is not currently annotated with this precise GO term. Reason: Histone chaperone activity is a core molecular function of NPM1 that is well-supported by multiple experimental studies but is not captured by any existing annotation at this level of specificity. The existing annotations cover histone binding (GO:0042393) and chromatin remodeling (GO:0006338) but not the specific chaperone activity. Supporting Evidence: PMID:11602260 Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to mediate formation of nucleosome, and to decondense sperm chromatin. These activities of B23 were dependent on its acidic regions as other histone chaperones, suggesting that B23/nucleophosmin is a member of histone chaperone proteins. PMID:16107701 Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription.

Core Functions

NPM1 functions as a histone chaperone for core histones H3, H2B, and H4, binding them through its acidic intrinsically disordered regions whose charge patterning mimics DNA. It mediates nucleosome assembly and disassembly, decondenses sperm chromatin, and enhances acetylation-dependent chromatin transcription by disrupting nucleosomal structure. This is an ATP-independent chaperone activity distinct from its general protein folding chaperone function. Histone chaperoning is a primary molecular activity of NPM1 in the nucleus, and is modulated by post-translational modifications including phosphorylation, acetylation, and SUMOylation (DOI:10.3390/cells13151266).

Molecular Function:

histone chaperone activity

Directly Involved In:

nucleosome assembly chromatin remodeling

Cellular Locations:

nucleolus nucleoplasm

Supporting Evidence:

PMID:11602260
Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to mediate formation of nucleosome, and to decondense sperm chromatin. These activities of B23 were dependent on its acidic regions as other histone chaperones, suggesting that B23/nucleophosmin is a member of histone chaperone proteins.
PMID:16107701
Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription. Presumably, nucleophosmin disrupts the nucleosomal structure in an acetylation-dependent manner, resulting in the transcriptional activation.

NPM1 is a rate-limiting nucleocytoplasmic shuttling chaperone that directly binds both large and small ribosomal subunits and mediates their CRM1/XPO1-dependent nuclear export. It associates with maturing nuclear 60S ribosomal subunits via ribosomal protein L5 and delivers them to the cytoplasm for assembly into functional 80S ribosomes and polysomes. NPM1 also acts as a nuclear import adaptor, shuttling cargo proteins such as ARID3C and HIV-1 Tat to the nucleolus. The Ran-Crm1 pathway controls NPM1 nucleocytoplasmic distribution. Within the nucleolus, NPM1 is a major driver of liquid-liquid phase separation (LLPS) in the granular component (GC), forming condensate droplets with arginine-rich proteins and rRNA that scaffold pre-ribosomal particle maturation. Oligomer stability, regulated by phosphorylation at sites such as Ser125, directly controls droplet fluidity and thus nucleolar dynamics (DOI:10.1101/2023.01.23.525122). This transport activity integrates NPM1 roles in nucleolar ribosome assembly with cytoplasmic ribosome delivery.

Molecular Function:

nucleocytoplasmic carrier activity

Directly Involved In:

ribosomal large subunit export from nucleus ribosomal small subunit export from nucleus ribosomal large subunit biogenesis ribosomal small subunit biogenesis nucleocytoplasmic transport

Cellular Locations:

nucleolus granular component cytoplasm

Supporting Evidence:

PMID:18809582
Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
PMID:16648475
Direct interaction of NPM with rpL5 mediated the colocalization of NPM with maturing nuclear 60S ribosomal subunits, as well as newly exported and assembled 80S ribosomes and polysomes.
PMID:18420587
Our results suggest that B23 selectively stores, and protects ribosomal protein S9 in nucleoli and therefore could facilitate ribosome biogenesis.

NPM1 exhibits general molecular chaperone activity independent of its histone chaperone function. It preferentially binds denatured protein substrates and prevents their aggregation (holdase activity), exposes hydrophobic regions when complexed with denatured proteins, and promotes restoration of enzyme activity after denaturation (foldase activity). This chaperone function is likely related to its roles in ribosome biogenesis where it assists in folding and protecting ribosomal proteins during assembly, including selective storage and protection of ribosomal protein S9 in the nucleolus.

Molecular Function:

protein folding chaperone

Directly Involved In:

ribosome biogenesis protein folding

Cellular Locations:

nucleolus

Supporting Evidence:

PMID:10211837
Protein B23 preferentially bound denatured substrates and exposed hydrophobic regions when complexed with denatured proteins. Protein B23 also protected liver alcohol dehydrogenase (LADH), carboxypeptidase A, citrate synthase, and rhodanese from aggregation during thermal denaturation. In addition, protein B23 was able to promote the restoration of activity of LADH previously denatured with guanidine-HCl.

NPM1 associates with unduplicated centrosomes and acts as a licensing factor for centrosome duplication by physically preventing premature centriole replication. NPM1 is a substrate of CDK2/cyclin E, which phosphorylates it at Thr199 triggering its dissociation from centrosomes and thereby licensing duplication. PLK2 further phosphorylates NPM1 at Ser4 in a Polo-box-dependent manner to trigger centriole duplication. The Ran-Crm1 pathway controls NPM1 centrosome association. Loss of NPM1 centrosome function leads to unrestricted centrosome duplication and genomic instability, a hallmark of cancer. This represents a fundamentally distinct core activity from NPM1 nucleolar functions.

Molecular Function:

protein kinase binding

Directly Involved In:

negative regulation of centrosome duplication regulation of centrosome duplication regulation of centriole replication centrosome cycle

Cellular Locations:

centrosome spindle pole centrosome

Supporting Evidence:

PMID:11051553
We identified nucleophosmin (NPM/B23) as a substrate of CDK2/cyclin E in centrosome duplication. NPM/B23 associates specifically with unduplicated centrosomes, and NPM/B23 dissociates from centrosomes by CDK2/cyclin E-mediated phosphorylation.
PMID:20352051
We find that Plk2 and NPM/B23 interact in vitro in a Polo-box dependent manner. Expression of a non-phosphorylatable NPM/B23 S4A mutant interferes with centriole reduplication in S-phase arrested cells and leads to a dilution of centriole numbers in unperturbed U2OS cells.
PMID:16041368
Ran-Crm1 controls NPM1 association with centrosomes for centrosome duplication regulation.

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10211837

Nucleolar protein B23 has molecular chaperone activities.

PMID:11051553

Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication.

PMID:11420665

Diverged nuclear localization of Werner helicase in human and mouse cells.

PMID:11602260

Function of nucleophosmin/B23, a nucleolar acidic protein, as a histone chaperone.

PMID:12058066

The RNA binding activity of a ribosome biogenesis factor, nucleophosmin/B23, is modulated by phosphorylation with a cell cycle-dependent kinase and by association with its subtype.

PMID:12080348

Nucleophosmin regulates the stability and transcriptional activity of p53.

PMID:12882984

Nucleophosmin interacts with and inhibits the catalytic function of eukaryotic initiation factor 2 kinase PKR.

PMID:15087454

Identification of nucleophosmin as an NF-kappaB co-activator for the induction of the human SOD2 gene.

PMID:15144954

Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation.

PMID:15161933

Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.

PMID:15184379

Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase.

PMID:15989956

ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor.

PMID:16041368

Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication.

PMID:16107701

Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription.

PMID:16130169

Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.

PMID:16376884

Characterisation of the interface between nucleophosmin (NPM) and p53: potential role in p53 stabilisation.

PMID:16540653

Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant.

PMID:16648475

Nucleophosmin is essential for ribosomal protein L5 nuclear export.

PMID:16957780

Antiviral action of the tumor suppressor ARF.

PMID:17015463

Interaction between ROCK II and nucleophosmin/B23 in the regulation of centrosome duplication.

PMID:17318229

Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation.

PMID:17353931

Large-scale mapping of human protein-protein interactions by mass spectrometry.

PMID:17438371

Detection and identification of transcription factors as interaction partners of alien in vivo.

PMID:17475909

The human Shwachman-Diamond syndrome protein, SBDS, associates with ribosomal RNA.

PMID:17602943

Physical and functional interaction between a nucleolar protein nucleophosmin/B23 and adenovirus basic core proteins.

PMID:18243139

The nucleocapsid protein of SARS-associated coronavirus inhibits B23 phosphorylation.

PMID:18259216

The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing.

PMID:18420587

Ribosomal protein S9 is a novel B23/NPM-binding protein required for normal cell proliferation.

PMID:18809582

Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.

PMID:19160485

A ribosomal protein L23-nucleophosmin circuit coordinates Mizl function with cell growth.

PMID:19188445

APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in the rRNA quality control process.

PMID:19208757

Nucleolar structure and function are regulated by the deubiquitylating enzyme USP36.

PMID:19410545

HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:20075868

Nucleolar retention of a translational C/EBPalpha isoform stimulates rDNA transcription and cell size.

PMID:20159986

Methylation of ribosomal protein S10 by protein-arginine methyltransferase 5 regulates ribosome biogenesis.

PMID:20352051

Polo-like kinase 2-dependent phosphorylation of NPM/B23 on serine 4 triggers centriole duplication.

PMID:20618440

Proteomic and biochemical analysis of 14-3-3-binding proteins during C2-ceramide-induced apoptosis.

PMID:20701745

Karyopherin alpha7 (KPNA7), a divergent member of the importin alpha family of nuclear import receptors.

PMID:21326211

The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex.

PMID:21423176

Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:21822216

Nucleophosmin deposition during mRNA 3' end processing influences poly(A) tail length.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:22510990

AKT-dependent phosphorylation of Niban regulates nucleophosmin- and MDM2-mediated p53 stability and cell apoptosis.

PMID:22528486

Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

PMID:22712502

Erythroid differentiation-associated gene interacts with NPM1 (nucleophosmin/B23) and increases its protein stability, resisting cell apoptosis.

PMID:22720776

PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex.

PMID:23019224

DDX31 regulates the p53-HDM2 pathway and rRNA gene transcription through its interaction with NPM1 in renal cell carcinomas.

PMID:23816991

Exploration of binary virus-host interactions using an infectious protein complementation assay.

PMID:23892143

Human respiratory syncytial virus N, P and M protein interactions in HEK-293T cells.

PMID:23972994

ABH2 couples regulation of ribosomal DNA transcription with DNA alkylation repair.

PMID:24106084

Intrinsically disordered regions of nucleophosmin/B23 regulate its RNA binding activity through their inter- and intra-molecular association.

PMID:24462683

Interaction between nucleophosmin and HBV core protein increases HBV capsid assembly.

PMID:24857377

Phosphorylation of multifunctional nucleolar protein nucleophosmin (NPM1) by aurora kinase B is critical for mitotic progression.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25956029

The Nucleolar Protein GLTSCR2 Is an Upstream Negative Regulator of the Oncogenic Nucleophosmin-MYC Axis.

PMID:26496610

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

PMID:28255170

Nucleophosmin Interacts with PIN2/TERF1-interacting Telomerase Inhibitor 1 (PinX1) and Attenuates the PinX1 Inhibition on Telomerase Activity.

PMID:28611246

Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy.

PMID:29568061

An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.

PMID:30021884

Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

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:35709258

Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity.

PMID:38029384

Proteomics analysis identifies the ribosome associated coiled-coil domain-containing protein-124 as a novel interaction partner of nucleophosmin-1.

PMID:38231884

ARID3C Acts as a Regulator of Monocyte-to-Macrophage Differentiation Interacting with NPM1.

PMID:39251607

Systematic identification of post-transcriptional regulatory modules.

PMID:9094689

Protein B23 is an important human factor for the nucleolar localization of the human immunodeficiency virus protein Tat.

PMID:9121481

Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.

Reactome:R-HSA-180725

Rev associates with B23

Reactome:R-HSA-180728

Association of Ran-GTP with importin-beta

Reactome:R-HSA-180736

Disassembly of the Rev-importin beta-B23:Ran-GTP complex

Reactome:R-HSA-4086059

SUMOylation of NPM1 with SUMO2,3

Reactome:R-HSA-4086088

SUMOylation of NPM1 with SUMO1

Reactome:R-HSA-606287

RSF complex binds the centromere

Reactome:R-HSA-606289

New CENPA-containing nucleosomes are deposited at the centromere

Reactome:R-HSA-606326

HJURP:CENPA complex localizes to the centromere

Reactome:R-HSA-6801675

PLK2 phosphorylates NPM1

Reactome:R-HSA-8869542

TFPA2A homodimer and NPM1 bind the HSPD1 gene promoter

Reactome:R-HSA-8869543

TFPA2A homodimer and NPM1 bind the NOP2 gene promoter

Reactome:R-HSA-8869549

TFPA2A homodimer and NPM1 bind the MYBL2 gene promoter

Reactome:R-HSA-8869568

NPM1 binds TFAP2A homodimer

Reactome:R-HSA-9700131

ALK mutants bind type I TKIs

Reactome:R-HSA-9700179

Ligand-independent dimerization of ALK fusions

Reactome:R-HSA-9700181

Autophosphorylation of ALK fusions

Reactome:R-HSA-9700190

ALK mutants bind SHC

Reactome:R-HSA-9700193

ALK mutants phosphorylate SHC1

Reactome:R-HSA-9710914

ALK fusions bind GRB2

Reactome:R-HSA-9710917

ALK fusion proteins bind PLCG1

Reactome:R-HSA-9712078

ALK mutants bind PI3KR1

Reactome:R-HSA-9712079

ALK mutants bind STAT3

Reactome:R-HSA-9712081

ALK fusions bind FRS

Reactome:R-HSA-9712082

ALK fusions phosphorylate IRS1

Reactome:R-HSA-9712083

ALK mutants bind PI3KCA

Reactome:R-HSA-9712084

PI3K synthesizes PIP3 downstream of ALK mutants

Reactome:R-HSA-9712085

ALK mutants phosphorylate STAT3

Reactome:R-HSA-9712086

ALK fusions phosphorylate PLCG1

Reactome:R-HSA-9712087

ALK fusions phosphorylate FRS

Reactome:R-HSA-9712088

ALK fusion proteins bind IRS

Reactome:R-HSA-9724099

ALK mutants:p-3Y SHC binds GRB2

Reactome:R-HSA-9725009

NPM1-ALK translocates to the nucleus

Reactome:R-HSA-9725023

NPM1-ALK fusion dimer binds SKP1:CUL1:RBX1:ZC3HC1

Reactome:R-HSA-9725030

MAPK1 phsophorylates ZC3HCF1 in a NPM-ALK-dependent manner

Reactome:R-HSA-9727886

SARS-CoV-1 SUMO-p-N binds to NPM1

Reactome:R-HSA-9835328

NPM binds PKR

Reactome:R-HSA-9850958

pY-STAT3 dimer translocates to the nucleus downstream of ALK mutants

Reactome:R-HSA-9851090

NPM1-ALK binds NPM1 and FOXM1

DOI:10.3390/cells13151266

Nucleophosmin: A Nucleolar Phosphoprotein Orchestrating Cellular Stress Responses

NPM1 is a modular protein with an N-terminal oligomerization domain, a central acidic/disordered region contributing to histone binding, and a C-terminal globular nucleic-acid-binding domain including nucleolar localization determinants (NoLS) and key aromatic residues (W288/W290).
NPM1 is a major driver of nucleolar LLPS, forming homotypic droplets and heterotypic droplets with arginine-rich proteins and rRNA that help establish nucleolar GC structure and ribosome-production capacity.
Oxidation and S-glutathionylation at Cys275 triggers NPM1 release from the nucleolus to the nucleoplasm during nucleolar stress responses.
NPM1 participates in DNA damage responses and repair pathway execution, including scaffolding/interaction with DNA repair factors and regulation by phosphorylation states, and interacts with p53/HDM2 regulatory circuits in the context of stress and genome stability.

DOI:10.1101/2023.01.23.525122

The stability of NPM1 oligomers regulated by acidic disordered regions controls the quality of liquid droplets

Destabilizing NPM1 oligomers (e.g. by altering acidic disordered regions or phosphomimetic changes at Ser125) increased droplet fluidity, supporting a model where post-translationally tuned oligomer stability helps regulate nucleolar dynamics across the cell cycle.

DOI:10.3390/ijms24043161

Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation

Common exon 12 frameshift mutations disrupt the C-terminal fold/NoLS (including loss of key aromatic residues W288/W290) and introduce/strengthen nuclear export, shifting NPM1 to the cytoplasm (NPM1c+), a hallmark visualizable by immunohistochemistry.

DOI:10.1158/2643-3230.bcd-23-0144

Criteria for Diagnosis and Molecular Monitoring of NPM1-Mutated AML

NPM1-mutated AML is the largest molecular subgroup of adult AML, accounting for approximately 30-35% of adult cases and enriched in normal-karyotype AML (approximately 50-60%).
NPM1 mutations are AML-specific and absent from preleukemic clonal hematopoiesis, making them particularly suitable MRD targets.

📚 Additional Documentation

Deep Research Falcon

(NPM1-deep-research-falcon.md)

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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: P06748
Protein Description: RecName: Full=Nucleophosmin; Short=NPM; AltName: Full=Nucleolar phosphoprotein B23; AltName: Full=Nucleolar protein NO38; AltName: Full=Numatrin;
Gene Information: Name=NPM1 {ECO:0000312|HGNC:HGNC:7910}; Synonyms=NPM;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the nucleoplasmin family. .
Key Domains: NPM1_C. (IPR032569); Nucleoplasmin. (IPR004301); Nucleoplasmin_core_dom. (IPR024057); Nucleoplasmin_core_dom_sf. (IPR036824); NPM1-C (PF16276)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "NPM1" 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 'NPM1' 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 NPM1 (gene ID: NPM1, UniProt: P06748) 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: P06748
Protein Description: RecName: Full=Nucleophosmin; Short=NPM; AltName: Full=Nucleolar phosphoprotein B23; AltName: Full=Nucleolar protein NO38; AltName: Full=Numatrin;
Gene Information: Name=NPM1 {ECO:0000312|HGNC:HGNC:7910}; Synonyms=NPM;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the nucleoplasmin family. .
Key Domains: NPM1_C. (IPR032569); Nucleoplasmin. (IPR004301); Nucleoplasmin_core_dom. (IPR024057); Nucleoplasmin_core_dom_sf. (IPR036824); NPM1-C (PF16276)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "NPM1" 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 NPM1 (gene ID: NPM1, UniProt: P06748) 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.

Comprehensive research report: Human NPM1 (nucleophosmin; UniProt P06748)

Target verification and scope

This report concerns human nucleophosmin (NPM1; synonyms B23/NO38/numatrin), a 294-aa (~37 kDa) nucleoplasmin-family protein (UniProt P06748 context) whose best-characterized cellular role is as an abundant nucleolar organizer/chaperone that supports ribosome biogenesis and nucleolar integrity, in part via liquid–liquid phase separation (LLPS), and whose most prominent clinical relevance is NPM1-mutated acute myeloid leukemia (AML) with cytoplasmic NPM1 (“NPM1c+”). (taha2024nucleophosminanucleolar pages 1-3, taha2024nucleophosminanucleolar pages 3-4)

Key concepts and definitions (current understanding)

2.1 Nucleolar organization and the granular component (GC)

The nucleolus is a membrane-less nuclear compartment where rRNA transcription/processing and ribosome subunit assembly occur; within the nucleolus, NPM1 is predominantly enriched in the granular component (GC), a region linked to late stages of pre-rRNA processing and ribosomal subunit maturation. (taha2024nucleophosminanucleolar pages 4-6)

2.2 Liquid–liquid phase separation (LLPS) and NPM1 as a nucleolar scaffold

NPM1 is widely viewed as a major driver of nucleolar LLPS, forming homotypic droplets and heterotypic droplets with arginine-rich proteins and/or rRNA; these condensate properties help explain how NPM1 contributes to nucleolar structure and ribosome-production capacity. (okuwaki2023thestabilityof pages 1-7, taha2024nucleophosminanucleolar pages 4-6)

2.3 Chaperone concepts applied to NPM1

NPM1 is described as a multifunctional molecular chaperone for both proteins and nucleic acids. In practice this includes histone chaperone activity (supporting nucleosome formation and chromatin remodeling) and broader protein/nucleic-acid chaperoning during stress and nucleolar/ribosome assembly. (taha2024nucleophosminanucleolar pages 1-3, taha2024nucleophosminanucleolar pages 10-12)

NPM1 protein architecture, domains, and structure-function links

3.1 Modular domain organization

Across recent reviews, NPM1 is described as a modular protein with: (i) an N-terminal oligomerization domain (OD) that supports assembly into pentamers and higher-order oligomers; (ii) a central acidic/disordered region that contributes to histone binding and regulation of interactions; and (iii) a C-terminal globular nucleic-acid-binding region (also described as an RNA-recognition domain) that includes nucleolar localization determinants (NoLS) and aromatic residues important for correct folding and nucleolar targeting. (taha2024nucleophosminanucleolar pages 3-4, okuwaki2023thestabilityof pages 1-7, chin2023targetingandmonitoring pages 2-5)

A schematic view of this domain architecture and its disruption in AML-associated mutants is shown in Chin et al. (2023). (chin2023targetingandmonitoring media 7f713754, chin2023targetingandmonitoring media 4ef58d28)

3.2 Oligomerization and control of condensate material properties (recent mechanistic insight)

A 2023 mechanistic study links oligomer stability to the “quality” (material properties) of NPM1-driven liquid droplets: destabilizing oligomers (e.g., by altering acidic disordered regions or phosphomimetic changes at Ser125) increased droplet fluidity, supporting a model where post-translationally tuned oligomer stability helps regulate nucleolar dynamics across the cell cycle. (okuwaki2023thestabilityof pages 1-7)

Subcellular localization and trafficking

4.1 Basal localization and shuttling

NPM1 is described as primarily nucleolar but dynamically shuttling between the nucleolus, nucleoplasm, and cytoplasm via nuclear localization signals (NLSs) and nuclear export signals (NESs). A key export pathway involves CRM1/XPO1 and RAN; one NES (often described as NES2) is highlighted as important for export control and is also discussed in relation to centrosome association. (taha2024nucleophosminanucleolar pages 3-4, taha2024nucleophosminanucleolar pages 4-6)

4.2 Stress-responsive relocalization

NPM1 is considered a stress sensor/regulator: multiple stresses (e.g., irradiation, UV, oxidative stress) alter NPM1 phosphorylation and/or localization; oxidation/S-glutathionylation at Cys275 is described as a trigger for release from the nucleolus to the nucleoplasm during nucleolar stress responses. (taha2024nucleophosminanucleolar pages 4-6, taha2024nucleophosminanucleolar pages 1-3)

Primary cellular functions and pathways (functional annotation narrative)

5.1 Ribosome biogenesis (central function)

NPM1’s best-supported primary cellular role is to support ribosome biogenesis and nucleolar structure.

Mechanistically, NPM1 is reported to regulate late pre-rRNA processing and ribosomal subunit assembly in the GC and to directly bind and assist nuclear export of ribosomal protein L5 (rpL5). Experimental perturbation of NPM1 impairs export of rpL5 and 5S rRNA, and reduces proliferation, consistent with an essential role in sustaining ribosome output. (taha2024nucleophosminanucleolar pages 4-6)

NPM1 is also described as an endoribonuclease contributing to processing steps toward mature 28S rRNA, and as a scaffold interacting with multiple ribosomal proteins. (chin2023targetingandmonitoring pages 2-5, taha2024nucleophosminanucleolar pages 3-4)

5.2 Chromatin and histone chaperone functions

NPM1 is described as a histone-binding protein whose acidic stretches can “mimic DNA,” supporting preferential binding to histone H3 and promoting nucleosome formation and chromatin decondensation. These functions provide a mechanistic route for NPM1 to influence transcription and genome organization, including nucleolus-associated chromatin states. (taha2024nucleophosminanucleolar pages 3-4)

5.3 Genome stability and DNA repair (recent review emphasis)

NPM1 has increasingly been highlighted as participating in DNA damage responses and repair pathway execution, including scaffolding/interaction with DNA repair factors and regulation by phosphorylation states; NPM1 is also described as interacting with p53/HDM2 regulatory circuits in the context of stress and genome stability. (taha2024nucleophosminanucleolar pages 4-6, taha2024nucleophosminanucleolar pages 10-12)

Regulation by post-translational modifications (PTMs)

Recent reviews emphasize that phosphorylation, acetylation, ubiquitination, SUMOylation, and oxidative modifications can regulate NPM1 oligomeric state, localization, and functional outputs.

Phosphorylation: multiple residues are highlighted as functionally important, including Ser4 (linked to centrosome/centriole duplication regulation), Ser48 (affecting localization), Ser125 (linked to oligomer stability/condensate properties), and Thr199 (linked to centrosome duplication and mitotic control and reduced RNA binding). Additional mitosis-linked phosphorylation sites (e.g., Thr234/Thr237) are associated with nucleolar disassembly/detachment. (taha2024nucleophosminanucleolar pages 4-6, okuwaki2023thestabilityof pages 1-7, taha2024nucleophosminanucleolar pages 3-4)

SUMOylation/ubiquitination/acetylation: NPM1 SUMOylation and deSUMOylation (e.g., SENP3-regulated) are described as influencing ribosome biogenesis and other nuclear functions; acetylation is described as favoring nucleoplasmic localization and modulating transcriptional activation; ubiquitination pathways (e.g., BRCA1–BARD1-related) are discussed as modulating NPM1 stability. (taha2024nucleophosminanucleolar pages 3-4, taha2024nucleophosminanucleolar pages 12-13)

Recent developments and latest research directions (2023–2024)

7.1 LLPS as a unifying framework for nucleolar homeostasis

The 2023 mechanistic linkage between NPM1 oligomer stability and droplet fluidity provides a concrete route by which phosphorylation and disordered-region charge patterning could tune nucleolar condensate behavior. This helps connect classical “nucleolar protein/chaperone” views of NPM1 to modern condensate/phase-separation models. (okuwaki2023thestabilityof pages 1-7)

7.2 Emerging view of NPM1 as a genome–nucleolus interface factor

Recent sources increasingly discuss NPM1 beyond ribosome biogenesis, emphasizing roles in genome organization and repair and positioning NPM1 as a hub integrating stress signals, chromatin regulation, and nucleolar function. (taha2024nucleophosminanucleolar pages 10-12, taha2024nucleophosminanucleolar pages 4-6)

Disease relevance and real-world implementations (focus: NPM1-mutated AML)

8.1 Defining lesion and epidemiology

NPM1-mutated AML is described as the largest molecular subgroup of adult AML, accounting for ~30–35% of adult cases; it is enriched in normal-karyotype AML (~50–60%) and is less frequent in children (~2–8%). (Falini & Dillon, Blood Cancer Discovery; publication date: Dec 2024; https://doi.org/10.1158/2643-3230.bcd-23-0144) (falini2024criteriafordiagnosis pages 1-2)

At the protein level, common exon 12 frameshift mutations disrupt the C-terminal fold/NoLS (including loss of key aromatic residues such as W288/W290) and introduce/strengthen nuclear export, shifting NPM1 to the cytoplasm (NPM1c+), a hallmark that can be visualized by immunohistochemistry and summarized schematically in recent reviews. (chin2023targetingandmonitoring pages 2-5, chin2023targetingandmonitoring media 7f713754)

8.2 Diagnostics and classification (2023–2024 perspective)

Recent expert reviews highlight changing classification criteria: WHO5 and ICC both treat NPM1 mutation as AML-defining, but may differ on blast-count thresholds, creating potential diagnostic discordance. (Patel, Pathobiology; publication date: Mar 2024; https://doi.org/10.1159/000530253) (patel2024npm1mutatedacutemyeloid pages 4-5)

8.3 Molecular monitoring / measurable residual disease (MRD) as a clinical tool

A key practical implementation is serial monitoring of mutant NPM1 transcripts. A 2024 expert review emphasizes that NPM1 mutations are AML-specific and (as framed by the authors) absent from preleukemic clonal hematopoiesis, making them particularly suitable MRD targets; ELN guidelines mandate NPM1 (and FLT3) testing for risk stratification and increasingly recommend MRD integration into management decisions. (Falini & Dillon, Dec 2024; https://doi.org/10.1158/2643-3230.bcd-23-0144) (falini2024criteriafordiagnosis pages 6-7, falini2024criteriafordiagnosis pages 1-2)

Methodologically, RT-qPCR is positioned as the established standard; ddPCR is highlighted for high sensitivity and practical quantification of rare mutant types without reliance on standard curves, whereas NGS-based MRD is described as less standardized and often less sensitive, especially from genomic DNA, and recommended mainly in clinical-trial contexts. (falini2024criteriafordiagnosis pages 6-7)

8.4 Outcomes data and statistics from recent studies

Venetoclax-based nonintensive therapy (real-world cohort, 2024): In 76 previously untreated NPM1-mutated AML patients achieving CR/CRi on venetoclax + HMA or venetoclax + LDAC, 58% achieved bone marrow MRD negativity; cumulative MRD negativity by cycles 2, 4, and 6 was 25%, 47%, and 50%, respectively. Patients who were MRD-negative by end of cycle 4 had 2-year OS 84% versus 46% if MRD-positive, and among those who electively stopped therapy in MRD-negative remission, 2-year treatment-free remission was 88%. (Othman et al., Blood; publication date: Jan 2024; https://doi.org/10.1182/blood.2023021579) (othman2024molecularmrdis pages 5-6)

Relapsed/refractory AML outcomes (2023): In a large single-center retrospective cohort of 1,722 relapsed/refractory AML patients, 12% (206) had NPM1c. Adding venetoclax to salvage regimens in NPM1c disease was associated with improved outcomes (median RFS 15.8 vs 4.6 months; median OS 14.7 vs 5.9 months). (Issa et al., Blood Advances; publication date: Mar 2023; https://doi.org/10.1182/bloodadvances.2022008316) (issa2023clinicaloutcomesassociated pages 1-2)

8.5 Targeted therapies and emerging strategies (expert synthesis)

Recent expert syntheses emphasize that NPM1c biology is linked to HOX/MEIS programs and that this dependency may help explain responses to emerging agents such as menin inhibitors and second-generation XPO1 inhibitors. A 2024 diagnostic/MRD review also cites clinical activity of the menin inhibitor revumenib in NPM1-mutated AML (reported 21% complete remissions, often with MRD negativity). (Falini & Dillon, Dec 2024; https://doi.org/10.1158/2643-3230.bcd-23-0144) (falini2024criteriafordiagnosis pages 1-2)

Expert opinions and interpretive analysis (authoritative sources)

9.1 NPM1 as an MRD “ideal target” and a decision tool—yet with implementation cautions

Falini & Dillon (2024) argue that NPM1 is an excellent MRD marker because it is common, AML-specific, and dynamically tracks disease burden; they also caution about inter-laboratory false positives and the need for rigorous assay validation and harmonization, and they note that MRD-guided transplant decisions remain incompletely supported by direct evidence in some risk subsets. (falini2024criteriafordiagnosis pages 6-7)

9.2 MRD negativity as a functional biomarker in venetoclax regimens

Othman et al. (2024) interpret early MRD negativity during venetoclax-based therapy as a strong prognostic marker that may enable treatment de-escalation/cessation strategies for selected patients, while emphasizing the need for prospective trials because indefinite therapy is common and cure is not proven. (othman2024molecularmrdis pages 8-9)

Limitations of the present evidence extraction

Quantitative biophysical constants (e.g., binding affinities, LLPS saturation concentrations, FRAP recovery half-times) were not present in the extracted text snippets available here; the most direct mechanistic quantitative directionality obtained was that droplet fluidity increases when oligomer stability decreases (e.g., Ser125 phosphomimetics), supporting regulation of nucleolar material properties by NPM1 oligomerization. (okuwaki2023thestabilityof pages 1-7)

Key citations (2023–2024 prioritized)
Taha MS, Ahmadian MR. “Nucleophosmin: A Nucleolar Phosphoprotein Orchestrating Cellular Stress Responses.” Cells. July 2024. https://doi.org/10.3390/cells13151266 (taha2024nucleophosminanucleolar pages 1-3, taha2024nucleophosminanucleolar pages 3-4)
Okuwaki M, et al. “The stability of NPM1 oligomers regulated by acidic disordered regions controls the quality of liquid droplets.” bioRxiv. Jan 2023. https://doi.org/10.1101/2023.01.23.525122 (okuwaki2023thestabilityof pages 1-7)
Chin L, et al. “Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation.” Int J Mol Sci. Feb 2023. https://doi.org/10.3390/ijms24043161 (chin2023targetingandmonitoring pages 2-5, chin2023targetingandmonitoring media 7f713754)
Falini B, Dillon R. “Criteria for Diagnosis and Molecular Monitoring of NPM1-Mutated AML.” Blood Cancer Discovery. Dec 2024. https://doi.org/10.1158/2643-3230.bcd-23-0144 (falini2024criteriafordiagnosis pages 1-2, falini2024criteriafordiagnosis pages 6-7)
Patel SS. “NPM1-Mutated Acute Myeloid Leukemia: Recent Developments and Open Questions.” Pathobiology. Mar 2024. https://doi.org/10.1159/000530253 (patel2024npm1mutatedacutemyeloid pages 4-5)
Othman J, et al. “Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based nonintensive therapy.” Blood. Jan 2024. https://doi.org/10.1182/blood.2023021579 (othman2024molecularmrdis pages 5-6)
Issa GC, et al. “Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML.” Blood Advances. Mar 2023. https://doi.org/10.1182/bloodadvances.2022008316 (issa2023clinicaloutcomesassociated pages 1-2)

References

(taha2024nucleophosminanucleolar pages 1-3): Mohamed S. Taha and Mohammad Reza Ahmadian. Nucleophosmin: a nucleolar phosphoprotein orchestrating cellular stress responses. Cells, 13:1266, Jul 2024. URL: https://doi.org/10.3390/cells13151266, doi:10.3390/cells13151266. This article has 19 citations.
(taha2024nucleophosminanucleolar pages 3-4): Mohamed S. Taha and Mohammad Reza Ahmadian. Nucleophosmin: a nucleolar phosphoprotein orchestrating cellular stress responses. Cells, 13:1266, Jul 2024. URL: https://doi.org/10.3390/cells13151266, doi:10.3390/cells13151266. This article has 19 citations.
(taha2024nucleophosminanucleolar pages 4-6): Mohamed S. Taha and Mohammad Reza Ahmadian. Nucleophosmin: a nucleolar phosphoprotein orchestrating cellular stress responses. Cells, 13:1266, Jul 2024. URL: https://doi.org/10.3390/cells13151266, doi:10.3390/cells13151266. This article has 19 citations.
(okuwaki2023thestabilityof pages 1-7): Mitsuru Okuwaki, Shin-Ichiro Ozawa, Shuhei Ebine, Motoki Juichi, Tadanobu Umeki, Kazuki Niioka, Taiyo Kikuchi, and Nobutada Tanaka. The stability of npm1 oligomers regulated by acidic disordered regions controls the quality of liquid droplets. bioRxiv, Jan 2023. URL: https://doi.org/10.1101/2023.01.23.525122, doi:10.1101/2023.01.23.525122. This article has 7 citations.
(taha2024nucleophosminanucleolar pages 10-12): Mohamed S. Taha and Mohammad Reza Ahmadian. Nucleophosmin: a nucleolar phosphoprotein orchestrating cellular stress responses. Cells, 13:1266, Jul 2024. URL: https://doi.org/10.3390/cells13151266, doi:10.3390/cells13151266. This article has 19 citations.
(chin2023targetingandmonitoring pages 2-5): Lynn Chin, Chantelle Ye Gwen Wong, and Harinder Gill. Targeting and monitoring acute myeloid leukaemia with nucleophosmin-1 (npm1) mutation. International Journal of Molecular Sciences, 24:3161, Feb 2023. URL: https://doi.org/10.3390/ijms24043161, doi:10.3390/ijms24043161. This article has 19 citations.
(chin2023targetingandmonitoring media 7f713754): Lynn Chin, Chantelle Ye Gwen Wong, and Harinder Gill. Targeting and monitoring acute myeloid leukaemia with nucleophosmin-1 (npm1) mutation. International Journal of Molecular Sciences, 24:3161, Feb 2023. URL: https://doi.org/10.3390/ijms24043161, doi:10.3390/ijms24043161. This article has 19 citations.
(chin2023targetingandmonitoring media 4ef58d28): Lynn Chin, Chantelle Ye Gwen Wong, and Harinder Gill. Targeting and monitoring acute myeloid leukaemia with nucleophosmin-1 (npm1) mutation. International Journal of Molecular Sciences, 24:3161, Feb 2023. URL: https://doi.org/10.3390/ijms24043161, doi:10.3390/ijms24043161. This article has 19 citations.
(taha2024nucleophosminanucleolar pages 12-13): Mohamed S. Taha and Mohammad Reza Ahmadian. Nucleophosmin: a nucleolar phosphoprotein orchestrating cellular stress responses. Cells, 13:1266, Jul 2024. URL: https://doi.org/10.3390/cells13151266, doi:10.3390/cells13151266. This article has 19 citations.
(falini2024criteriafordiagnosis pages 1-2): Brunangelo Falini and Richard Dillon. Criteria for diagnosis and molecular monitoring of npm1-mutated aml. Blood Cancer Discovery, 5:8-20, Dec 2024. URL: https://doi.org/10.1158/2643-3230.bcd-23-0144, doi:10.1158/2643-3230.bcd-23-0144. This article has 37 citations and is from a peer-reviewed journal.
(patel2024npm1mutatedacutemyeloid pages 4-5): Sanjay S. Patel. Npm1-mutated acute myeloid leukemia: recent developments and open questions. Pathobiology, 91:18-29, Mar 2024. URL: https://doi.org/10.1159/000530253, doi:10.1159/000530253. This article has 22 citations and is from a peer-reviewed journal.
(falini2024criteriafordiagnosis pages 6-7): Brunangelo Falini and Richard Dillon. Criteria for diagnosis and molecular monitoring of npm1-mutated aml. Blood Cancer Discovery, 5:8-20, Dec 2024. URL: https://doi.org/10.1158/2643-3230.bcd-23-0144, doi:10.1158/2643-3230.bcd-23-0144. This article has 37 citations and is from a peer-reviewed journal.
(othman2024molecularmrdis pages 5-6): Jad Othman, Ing S. Tiong, Jenny O'Nions, Mike Dennis, Katya Mokretar, Adam Ivey, Michael Austin, Anne-Louise Latif, Mariam Amer, Wei Yee Chan, Charles Crawley, Francesca Crolla, Joe Cross, Ray Dang, Johnathon Elliot, Chun Y. Fong, Sofia Galli, Paolo Gallipoli, Francesca Hogan, Pallavi Kalkur, Anjum Khan, Pramila Krishnamurthy, John Laurie, Sun Loo, Scott Marshall, Priyanka Mehta, Vidhya Murthy, Sateesh Nagumantry, Srinivas Pillai, Nicola Potter, Rob Sellar, Tom Taylor, Rui Zhao, Nigel H. Russell, Andrew H. Wei, and Richard Dillon. Molecular mrd is strongly prognostic in patients with npm1-mutated aml receiving venetoclax-based nonintensive therapy. Blood, 143:336-341, Jan 2024. URL: https://doi.org/10.1182/blood.2023021579, doi:10.1182/blood.2023021579. This article has 71 citations and is from a highest quality peer-reviewed journal.
(issa2023clinicaloutcomesassociated pages 1-2): Ghayas C. Issa, Aram Bidikian, Sangeetha Venugopal, Marina Konopleva, Courtney D. DiNardo, Tapan M. Kadia, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Musa Yilmaz, Nicholas J. Short, Abhishek Maiti, Koji Sasaki, Lucia Masarova, Sherry Pierce, Koichi Takahashi, Guilin Tang, Sanam Loghavi, Keyur Patel, Michael Andreeff, Kapil Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, and Naval Daver. Clinical outcomes associated with npm1 mutations in patients with relapsed or refractory aml. Blood Advances, 7:933-942, Mar 2023. URL: https://doi.org/10.1182/bloodadvances.2022008316, doi:10.1182/bloodadvances.2022008316. This article has 54 citations and is from a peer-reviewed journal.
(othman2024molecularmrdis pages 8-9): Jad Othman, Ing S. Tiong, Jenny O'Nions, Mike Dennis, Katya Mokretar, Adam Ivey, Michael Austin, Anne-Louise Latif, Mariam Amer, Wei Yee Chan, Charles Crawley, Francesca Crolla, Joe Cross, Ray Dang, Johnathon Elliot, Chun Y. Fong, Sofia Galli, Paolo Gallipoli, Francesca Hogan, Pallavi Kalkur, Anjum Khan, Pramila Krishnamurthy, John Laurie, Sun Loo, Scott Marshall, Priyanka Mehta, Vidhya Murthy, Sateesh Nagumantry, Srinivas Pillai, Nicola Potter, Rob Sellar, Tom Taylor, Rui Zhao, Nigel H. Russell, Andrew H. Wei, and Richard Dillon. Molecular mrd is strongly prognostic in patients with npm1-mutated aml receiving venetoclax-based nonintensive therapy. Blood, 143:336-341, Jan 2024. URL: https://doi.org/10.1182/blood.2023021579, doi:10.1182/blood.2023021579. This article has 71 citations and is from a highest quality peer-reviewed journal.

Citations

taha2024nucleophosminanucleolar pages 4-6
okuwaki2023thestabilityof pages 1-7
taha2024nucleophosminanucleolar pages 3-4
falini2024criteriafordiagnosis pages 1-2
falini2024criteriafordiagnosis pages 6-7
othman2024molecularmrdis pages 5-6
issa2023clinicaloutcomesassociated pages 1-2
othman2024molecularmrdis pages 8-9
taha2024nucleophosminanucleolar pages 1-3
taha2024nucleophosminanucleolar pages 10-12
chin2023targetingandmonitoring pages 2-5
taha2024nucleophosminanucleolar pages 12-13
https://doi.org/10.1158/2643-3230.bcd-23-0144
https://doi.org/10.1159/000530253
https://doi.org/10.1182/blood.2023021579
https://doi.org/10.1182/bloodadvances.2022008316
https://doi.org/10.3390/cells13151266
https://doi.org/10.1101/2023.01.23.525122
https://doi.org/10.3390/ijms24043161
https://doi.org/10.3390/cells13151266,
https://doi.org/10.1101/2023.01.23.525122,
https://doi.org/10.3390/ijms24043161,
https://doi.org/10.1158/2643-3230.bcd-23-0144,
https://doi.org/10.1159/000530253,
https://doi.org/10.1182/blood.2023021579,
https://doi.org/10.1182/bloodadvances.2022008316,

📄 View Raw YAML

id: P06748
gene_symbol: NPM1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Nucleophosmin (NPM1/B23) is an abundant, multifunctional nucleolar phosphoprotein
  involved in ribosome biogenesis, centrosome duplication, histone chaperoning, protein
  chaperoning, cell proliferation, genomic stability, and regulation of tumor suppressors
  p53/TP53 and ARF. It functions as a pentamer/decamer and shuttles between the nucleolus,
  nucleoplasm, and cytoplasm via CRM1/XPO1-dependent nuclear export. NPM1 is modular,
  comprising an N-terminal oligomerization domain (OD) that assembles pentamers and
  higher-order oligomers, a central acidic intrinsically disordered region (IDR) that
  mediates histone binding and regulates interactions, and a C-terminal globular
  nucleic-acid-binding domain containing the nucleolar localization signal (NoLS) and
  key aromatic residues (W288/W290) essential for nucleolar targeting
  (DOI:10.3390/cells13151266, DOI:10.3390/ijms24043161). NPM1 is a major driver of
  nucleolar liquid-liquid phase separation (LLPS), forming homotypic and heterotypic
  condensate droplets with arginine-rich proteins and rRNA that help establish nucleolar
  granular component (GC) structure and ribosome-production capacity. A 2023 mechanistic
  study demonstrated that oligomer stability, tunable by phosphorylation (e.g. Ser125
  phosphomimetics) and acidic IDR charge patterning, controls droplet fluidity, providing
  a concrete route by which post-translational modifications regulate nucleolar dynamics
  across the cell cycle (DOI:10.1101/2023.01.23.525122). NPM1 acts as a histone chaperone
  for core histones H3, H2B, and H4, and also exhibits broader molecular chaperone
  activity preventing protein aggregation and promoting refolding of denatured proteins.
  It serves as a rate-limiting nuclear export chaperone for ribosomal subunits.
  Stress-responsive relocalization occurs via oxidation and S-glutathionylation at Cys275,
  which triggers NPM1 release from the nucleolus to the nucleoplasm during nucleolar
  stress responses (DOI:10.3390/cells13151266). NPM1 increasingly is recognized as
  participating in DNA damage responses and repair pathway execution, interacting with
  p53/HDM2 regulatory circuits in the context of stress and genome stability
  (DOI:10.3390/cells13151266). Mutations in NPM1 exon 12 causing aberrant cytoplasmic
  localization (NPM1c+) are among the most common genetic alterations in acute myeloid
  leukemia (AML), accounting for approximately 30-35% of adult AML cases and enriched in
  normal-karyotype AML (approximately 50-60%); these mutations disrupt the C-terminal
  fold/NoLS and introduce a nuclear export signal, shifting NPM1 to the cytoplasm
  (DOI:10.1158/2643-3230.bcd-23-0144). NPM1 is also involved in the NPM1-ALK fusion
  oncogene in anaplastic large cell lymphoma.
alternative_products:
- name: '1'
  id: P06748-1
- name: '2'
  id: P06748-2
  sequence_note: VSP_003616
- name: '3'
  id: P06748-3
  sequence_note: VSP_043599
existing_annotations:
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 is a well-established histone chaperone that binds core histones H3, H2B, and H4
      (PMID:11602260, PMID:16107701), mediates nucleosome assembly/disassembly, and enhances
      acetylation-dependent chromatin transcription. Chromatin binding is consistent with its
      histone chaperone function. The IBA annotation is phylogenetically supported and appropriate.
    action: ACCEPT
    reason: >-
      NPM1 directly binds histones and chromatin as part of its histone chaperone activity.
      PMID:16107701 showed NPM1 enhances acetylation-dependent chromatin transcription, and
      PMID:11602260 demonstrated histone binding and nucleosome assembly. Chromatin binding
      is a core function.
    supported_by:
    - reference_id: PMID:16107701
      supporting_text: >-
        Human histone chaperone nucleophosmin interacts with the core histones H3, H2B, and H4
        but that this histone interaction is not sufficient to confer the chaperone activity.
    - reference_id: PMID:11602260
      supporting_text: >-
        Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to
        mediate formation of nucleosome, and to decondense sperm chromatin.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 is primarily nucleolar but translocates to the nucleoplasm under various conditions
      including serum starvation, anticancer drug treatment, and DNA damage. UniProt confirms
      nucleoplasm localization (ECO:0000269|PubMed:25818168). The IBA annotation is appropriate.
    action: ACCEPT
    reason: >-
      NPM1 is well-documented to localize to the nucleoplasm, particularly under stress conditions.
      Multiple IDA evidence supports this localization.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is
      mediated by RNA binding activity of the C-terminal domain (PMID:24106084). Multiple
      IDA annotations confirm nucleolar localization. This is a core localization for NPM1.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1 and is essential for its core functions
      in ribosome biogenesis and histone chaperoning.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 is a nucleocytoplasmic shuttling protein. It is found in the cytoplasm both
      during normal shuttling (PMID:9121481) and aberrantly in AML with NPM1c mutations.
      IDA evidence from PMID:9121481 confirms cytoplasmic localization.
    action: ACCEPT
    reason: >-
      NPM1 shuttles between nucleus and cytoplasm as part of its function in ribosome export
      and other transport roles. Cytoplasmic localization is well-established.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 binds RNA, particularly rRNA, through its C-terminal domain and intrinsically
      disordered basic region (PMID:24106084, PMID:12058066). RNA binding is modulated by
      phosphorylation and is essential for nucleolar localization and ribosome biogenesis.
      This is a core molecular function of NPM1.
    action: ACCEPT
    reason: >-
      RNA binding is a core function of NPM1 essential for ribosome biogenesis. Well-supported
      by multiple direct assay experiments.
    supported_by:
    - reference_id: PMID:24106084
      supporting_text: >-
        Nucleophosmin (NPM1/B23) is a nucleolar protein implicated in growth-associated
        functions, in which the RNA binding activity of B23 plays essential roles in
        ribosome biogenesis.
    - reference_id: PMID:12058066
      supporting_text: >-
        It has been shown that B23 binds to nucleic acids, digests RNA, and is localized in
        nucleolar granular components from which preribosomal particles are transported to cytoplasm.
- term:
    id: GO:0042393
    label: histone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 binds core histones H3, H2B, and H4 as part of its histone chaperone activity
      (PMID:11602260, PMID:16107701). Histone binding is a core molecular function of NPM1
      and is prerequisite for its nucleosome assembly activity.
    action: ACCEPT
    reason: >-
      Histone binding is a core function of NPM1, directly demonstrated by IDA in PMID:11602260.
    supported_by:
    - reference_id: PMID:11602260
      supporting_text: >-
        Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to
        mediate formation of nucleosome, and to decondense sperm chromatin.
- term:
    id: GO:0006338
    label: chromatin remodeling
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 functions as a histone chaperone that mediates nucleosome assembly/disassembly and
      enhances acetylation-dependent chromatin transcription (PMID:16107701). It also decondenses
      sperm chromatin (PMID:11602260). These activities constitute chromatin remodeling. The
      IBA annotation is phylogenetically supported and appropriate.
    action: ACCEPT
    reason: >-
      NPM1 is a histone chaperone involved in nucleosome dynamics and chromatin structure changes.
      Multiple studies support a role in chromatin remodeling.
    supported_by:
    - reference_id: PMID:16107701
      supporting_text: >-
        Presumably, nucleophosmin disrupts the nucleosomal structure in an acetylation-dependent
        manner, resulting in the transcriptional activation.
- term:
    id: GO:0000055
    label: ribosomal large subunit export from nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 serves as a rate-limiting nuclear export chaperone for ribosomal subunits
      (PMID:18809582). It directly binds ribosomal large subunits and mediates their export
      via CRM1-dependent pathway. PMID:16648475 showed NPM1 is essential for ribosomal protein
      L5 nuclear export and associates with maturing nuclear 60S ribosomal subunits. This is
      a core function of NPM1.
    action: ACCEPT
    reason: >-
      Ribosomal large subunit export is a core function of NPM1, directly demonstrated by
      multiple experimental studies.
    supported_by:
    - reference_id: PMID:18809582
      supporting_text: >-
        Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
    - reference_id: PMID:16648475
      supporting_text: >-
        Direct interaction of NPM with rpL5 mediated the colocalization of NPM with
        maturing nuclear 60S ribosomal subunits, as well as newly exported and assembled
        80S ribosomes and polysomes.
- term:
    id: GO:0000056
    label: ribosomal small subunit export from nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 binds ribosomal small subunits (PMID:18809582) and serves as a nuclear export
      chaperone for ribosomal subunits. The IBA annotation is phylogenetically supported.
    action: ACCEPT
    reason: >-
      PMID:18809582 demonstrated NPM1 binds both ribosomal large and small subunits and
      serves as a rate-limiting export chaperone.
    supported_by:
    - reference_id: PMID:18809582
      supporting_text: >-
        Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 associates with unduplicated centrosomes and dissociates upon CDK2/cyclin E-mediated
      phosphorylation to initiate centrosome duplication (PMID:11051553). UniProt confirms
      centrosome localization. Multiple IDA annotations support this.
    action: ACCEPT
    reason: >-
      Centrosome localization is well-established for NPM1 and is functionally important for
      regulating centrosome duplication.
    supported_by:
    - reference_id: PMID:11051553
      supporting_text: >-
        NPM/B23 associates specifically with unduplicated centrosomes, and NPM/B23 dissociates
        from centrosomes by CDK2/cyclin E-mediated phosphorylation.
- term:
    id: GO:0010824
    label: regulation of centrosome duplication
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 negatively regulates centrosome duplication by associating with unduplicated
      centrosomes; its dissociation after phosphorylation by CDK2/cyclin E initiates duplication
      (PMID:11051553). PLK2 phosphorylation of NPM1 at Ser4 triggers centriole duplication
      (PMID:20352051). Ran-Crm1 controls NPM1 association with centrosomes (PMID:16041368).
      This is a core function of NPM1.
    action: ACCEPT
    reason: >-
      Regulation of centrosome duplication is a well-established core function of NPM1,
      supported by multiple experimental studies in high-impact journals.
    supported_by:
    - reference_id: PMID:11051553
      supporting_text: >-
        We identified nucleophosmin (NPM/B23) as a substrate of CDK2/cyclin E in centrosome
        duplication. NPM/B23 associates specifically with unduplicated centrosomes, and NPM/B23
        dissociates from centrosomes by CDK2/cyclin E-mediated phosphorylation.
    - reference_id: PMID:20352051
      supporting_text: >-
        Plk2 phosphorylates NPM/B23 on serine 4
- term:
    id: GO:0042273
    label: ribosomal large subunit biogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 is essential for ribosomal large subunit biogenesis. It binds the large ribosomal
      subunit (PMID:18809582), is essential for ribosomal protein L5 nuclear export
      (PMID:16648475), and stores/protects ribosomal protein S9 in nucleoli (PMID:18420587).
      This is a core function.
    action: ACCEPT
    reason: >-
      Ribosome biogenesis is one of the most well-established core functions of NPM1.
    supported_by:
    - reference_id: PMID:18809582
      supporting_text: >-
        Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
    - reference_id: PMID:16648475
      supporting_text: >-
        Nucleophosmin is essential for ribosomal protein L5 nuclear export.
- term:
    id: GO:0042274
    label: ribosomal small subunit biogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 binds the small ribosomal subunit (PMID:18809582) and interacts with ribosomal
      protein S9 to facilitate its nucleolar storage and ribosome biogenesis (PMID:18420587).
      The IBA annotation is phylogenetically supported.
    action: ACCEPT
    reason: >-
      NPM1 is involved in both large and small ribosomal subunit biogenesis through its
      chaperone and export functions.
    supported_by:
    - reference_id: PMID:18420587
      supporting_text: >-
        Our results suggest that B23 selectively stores, and protects ribosomal protein S9
        in nucleoli and therefore could facilitate ribosome biogenesis.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 acts as a transcription coactivator. It enhances acetylation-dependent chromatin
      transcription (PMID:16107701), acts as an NF-kappaB coactivator for SOD2 induction
      (PMID:15087454), and in complex with MYC enhances MYC target gene transcription
      (PMID:25956029). However, NPM1 can also act as a transcriptional corepressor with
      AP2alpha (PMID:17318229). The positive regulation annotation is appropriate but represents
      a non-core pleiotropic function rather than a core molecular activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transcriptional coactivation is a documented activity of NPM1 but is secondary to its
      core histone chaperone and ribosome biogenesis functions.
- term:
    id: GO:1990904
    label: ribonucleoprotein complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NPM1 is associated with ribonucleoprotein complexes, consistent with its role in
      ribosome biogenesis and its binding to ribosomal subunits (PMID:18809582). IDA
      evidence from PMID:18809582 supports this localization.
    action: ACCEPT
    reason: >-
      NPM1 is a component of ribonucleoprotein complexes as part of its core role in
      ribosome biogenesis.
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      NPM1 binds both RNA (rRNA, mRNA) and DNA. This IEA annotation to nucleic acid
      binding is a parent of the more specific RNA binding (GO:0003723) already accepted
      via IBA. While correct, it is redundant with more specific annotations.
    action: ACCEPT
    reason: >-
      NPM1 binds nucleic acids broadly. The IEA is consistent with accepted IBA for
      RNA binding. Acceptable as a broader IEA even though more specific terms exist.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation duplicating the IBA for RNA binding already accepted. NPM1 RNA binding
      is well-established experimentally (PMID:24106084, PMID:12058066).
    action: ACCEPT
    reason: >-
      Consistent with IBA and IDA evidence for RNA binding. Redundant but not incorrect.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for nucleoplasm. NPM1 translocates to the nucleoplasm under stress
      or serum starvation. Consistent with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is well-established for NPM1. Redundant with IBA but correct.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for nucleolus. NPM1 is one of the most abundant nucleolar proteins.
      Redundant with IBA and many IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Correct and consistent.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for centrosome. NPM1 associates with unduplicated centrosomes
      (PMID:11051553). Consistent with IBA and IDA annotations.
    action: ACCEPT
    reason: >-
      Centrosome localization is well-established. Redundant but correct.
- term:
    id: GO:0010604
    label: positive regulation of macromolecule metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      Very broad IEA annotation. NPM1 does positively regulate macromolecule metabolism
      through its roles in ribosome biogenesis and transcription coactivation. However,
      this term is too general to be informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While technically correct, this is an extremely broad term that adds no informative
      value beyond what is captured by more specific annotations for ribosome biogenesis
      and transcription regulation.
- term:
    id: GO:0042127
    label: regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      NPM1 regulates cell proliferation through multiple mechanisms including ribosome
      biogenesis, centrosome duplication, p53 regulation, and ATF5 degradation
      (PMID:22528486, PMID:12080348). This is a pleiotropic downstream consequence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell proliferation regulation is an indirect consequence of NPM1 core functions
      (ribosome biogenesis, centrosome duplication, p53/ARF regulation). Not a core
      molecular function but is well-supported.
- term:
    id: GO:0042254
    label: ribosome biogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for ribosome biogenesis. NPM1 is central to ribosome biogenesis
      through rRNA processing, ribosomal protein chaperoning, and ribosomal subunit
      export (PMID:18809582, PMID:16648475, PMID:18420587). Consistent with IBA
      annotations for large and small subunit biogenesis.
    action: ACCEPT
    reason: >-
      Ribosome biogenesis is a core function of NPM1. This is a parent term of the
      more specific subunit biogenesis terms already accepted.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for negative regulation of apoptosis. NPM1 inhibits apoptosis
      through PKR inhibition (PMID:12882984) and p53 regulation. This is a pleiotropic
      downstream effect.
    action: KEEP_AS_NON_CORE
    reason: >-
      Anti-apoptotic activity is a secondary consequence of NPM1 core functions,
      particularly PKR inhibition. Well-supported but not a core molecular activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15144954
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:15144954 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15161933
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:15161933 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15989956
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:15989956 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16376884
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:16376884 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16540653
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:16540653 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16957780
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:16957780 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17318229
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:17318229 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:17353931 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17602943
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:17602943 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18243139
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:18243139 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18259216
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:18259216 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20618440
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:20618440 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20701745
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:20701745 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21326211
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:21326211 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21822216
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:21822216 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:21988832 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22510990
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:22510990 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22712502
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:22712502 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23816991
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:23816991 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23892143
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:23892143 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24462683
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:24462683 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24857377
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:24857377 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:25416956 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:26496610 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28255170
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:28255170 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28611246
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:28611246 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29568061
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:29568061 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:30021884 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:31515488 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:32296183 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:32814053 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:33961781 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:35271311 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35709258
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:35709258 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38029384
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:38029384 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:39251607
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:39251607 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0001652
    label: granular component
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for granular component of the nucleolus. NPM1 co-localizes with methylated RPS10 in the GC region (UniProt). The GC is where pre-ribosomal particles mature, consistent with NPM1 ribosome biogenesis role.
    action: ACCEPT
    reason: >-
      NPM1 is well-documented to localize in the granular component of the nucleolus where pre-ribosomal particles are assembled. Consistent with core function.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for nucleus. NPM1 is primarily a nuclear protein (nucleolar). This is a very broad term but consistent with multiple IDA annotations.
    action: ACCEPT
    reason: >-
      NPM1 is a nuclear protein. Correct and consistent, though very broad.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for cytoplasm. NPM1 shuttles to the cytoplasm as part of ribosome export function (PMID:9121481). Consistent with IBA annotation.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is consistent with NPM1 nucleocytoplasmic shuttling. Redundant with IBA but correct.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for cytosol. NPM1 can be found in the cytosol as part of its shuttling function and in the NPM1-ALK fusion context.
    action: ACCEPT
    reason: >-
      Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling. More specific than cytoplasm.
- term:
    id: GO:0015934
    label: large ribosomal subunit
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for large ribosomal subunit localization. NPM1 directly binds the large ribosomal subunit as part of its nuclear export chaperone function (PMID:18809582, PMID:16648475).
    action: ACCEPT
    reason: >-
      NPM1 associates with maturing 60S ribosomal subunits. Consistent with its ribosome export chaperone function.
- term:
    id: GO:0015935
    label: small ribosomal subunit
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for small ribosomal subunit localization. NPM1 binds both large and small ribosomal subunits (PMID:18809582).
    action: ACCEPT
    reason: >-
      NPM1 binds small ribosomal subunits. Consistent with its rate-limiting ribosome export chaperone role.
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for nuclear speck localization. While NPM1 is primarily nucleolar, some evidence suggests it may transiently associate with nuclear speckles. However, this is not well-established as a core localization.
    action: UNDECIDED
    reason: >-
      Nuclear speck localization for NPM1 is not well-characterized in the primary literature. The IEA transfer may be based on weak or indirect evidence. Unable to confirm without access to the original ortholog data.
- term:
    id: GO:0019843
    label: rRNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for rRNA binding. NPM1 binds rRNA through its C-terminal domain and intrinsically disordered basic region (PMID:24106084). This is more specific than the accepted RNA binding and directly supports ribosome biogenesis.
    action: ACCEPT
    reason: >-
      rRNA binding is a well-established core function of NPM1. More specific than the accepted RNA binding term.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for identical protein binding. NPM1 forms pentamers and decamers through homooligomerization (PMID:24106084, PMID:9121481). This is confirmed by IDA for protein homodimerization activity.
    action: ACCEPT
    reason: >-
      NPM1 oligomerization is a fundamental property. Consistent with IDA for homodimerization. Oligomerization is essential for NPM1 function.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for positive regulation of transcription by Pol II. Redundant with the IBA and IDA annotations for this term already reviewed.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transcriptional coactivation is a non-core pleiotropic function of NPM1. Redundant with IBA annotation already reviewed.
- term:
    id: GO:1904751
    label: positive regulation of protein localization to nucleolus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IEA annotation for positive regulation of protein localization to nucleolus. NPM1 mediates nucleolar localization of several proteins including HIV Tat (PMID:9094689), ribosomal proteins (PMID:18420587), and WRN helicase. This is consistent with its chaperoning/shuttling function.
    action: ACCEPT
    reason: >-
      NPM1 acts as a chaperone/shuttle for nucleolar localization of multiple proteins. Well-supported by multiple studies.
- term:
    id: GO:0004860
    label: protein kinase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:12882984
  review:
    summary: >-
      NPM1 inhibits PKR (EIF2AK2) autophosphorylation and catalytic function in a dose-dependent manner (PMID:12882984). Overexpression of NPM suppressed PKR activity, enhanced protein synthesis, and inhibited apoptosis. This is a specific molecular function.
    action: ACCEPT
    reason: >-
      PMID:12882984 directly demonstrated that recombinant NPM inhibited PKR activation in kinase assays. This is a genuine enzymatic inhibitor activity.
    supported_by:
    - reference_id: PMID:12882984
      supporting_text: >-
        Kinase assays demonstrated that recombinant NPM inhibited PKR activation in a
        dose-dependent manner.
- term:
    id: GO:0007249
    label: canonical NF-kappaB signal transduction
  evidence_type: IMP
  original_reference_id: PMID:15087454
  review:
    summary: >-
      PMID:15087454 showed NPM1 acts as an NF-kappaB coactivator for SOD2 gene induction. NPM physically interacts with NF-kappaB and increasing NPM expression leads to increased SOD2 transcription. This represents involvement in NF-kappaB signaling.
    action: KEEP_AS_NON_CORE
    reason: >-
      NF-kappaB signaling involvement is a pleiotropic downstream effect of NPM1 transcription coactivator function. Not a core molecular function.
    supported_by:
    - reference_id: PMID:15087454
      supporting_text: >-
        Co-immunoprecipitation studies suggest a physical interaction between NPM and
        NF-kappaB proteins.
- term:
    id: GO:2000767
    label: positive regulation of cytoplasmic translation
  evidence_type: IDA
  original_reference_id: PMID:12882984
  review:
    summary: >-
      PMID:12882984 showed that overexpression of NPM enhanced protein synthesis by inhibiting PKR, which normally phosphorylates eIF2alpha to suppress translation. This is an indirect effect mediated through PKR inhibition.
    action: KEEP_AS_NON_CORE
    reason: >-
      Enhanced translation is a downstream consequence of PKR inhibition by NPM1, not a direct translational regulation activity.
    supported_by:
    - reference_id: PMID:12882984
      supporting_text: >-
        Overexpression of NPM suppressed PKR activity, enhanced protein synthesis, and
        inhibited apoptosis.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IDA annotation based on immunofluorescence data curation (GO_REF:0000052). NPM1 is found in the nucleoplasm under stress or specific conditions. Consistent with IBA and other IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is well-established for NPM1 across multiple evidence types.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IDA annotation based on immunofluorescence data curation. NPM1 is one of the most abundant nucleolar proteins. Consistent with IBA and many other IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many studies.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:38231884
  review:
    summary: >-
      IDA annotation for nucleus from PMID:38231884 which studied ARID3C-NPM1 interaction. NPM1 was shown to shuttle between cytoplasm and nucleus, mediating ARID3C nuclear import.
    action: ACCEPT
    reason: >-
      Nuclear localization of NPM1 is well-established. PMID:38231884 confirmed NPM1 is nuclear.
- term:
    id: GO:0006606
    label: protein import into nucleus
  evidence_type: IDA
  original_reference_id: PMID:38231884
  review:
    summary: >-
      PMID:38231884 demonstrated that NPM1 mediates ARID3C nuclear shuttling. ARID3C forms a complex with NPM1 to translocate to the nucleus. When the ARID3C-NPM1 binding site was mutated, ARID3C was retained in the cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: >-
      NPM1 acts as a nuclear import adaptor for ARID3C. This is consistent with NPM1 general protein chaperoning function but is a specific case, not a core function.
    supported_by:
    - reference_id: PMID:38231884
      supporting_text: >-
        ARID3C forms a complex with NPM1 to translocate to the nucleus, acting as a
        transcription factor that promotes the expression of the genes involved in
        monocyte-to-macrophage differentiation.
- term:
    id: GO:0030225
    label: macrophage differentiation
  evidence_type: IDA
  original_reference_id: PMID:38231884
  review:
    summary: >-
      PMID:38231884 showed ARID3C-NPM1 complex promotes monocyte-to-macrophage differentiation. NPM1 role is as an adaptor for ARID3C nuclear import, not a direct driver of macrophage differentiation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      NPM1 is an adaptor for ARID3C nuclear import. The macrophage differentiation activity is primarily driven by ARID3C as transcription factor, not by NPM1 directly. This annotation over-attributes the differentiation process to NPM1.
    supported_by:
    - reference_id: PMID:38231884
      supporting_text: >-
        ARID3C was found to predominantly localize with the nucleus, where it functioned as
        a transcription factor for genes STAT3, STAT1, and JUNB, thereby facilitating
        monocyte-to-macrophage differentiation.
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:38231884
  review:
    summary: >-
      PMID:38231884 demonstrated NPM1 acts as an adaptor for ARID3C nuclear shuttling. NPM1 brings ARID3C to the nucleus through selective binding. This represents a genuine adaptor function.
    action: ACCEPT
    reason: >-
      NPM1 acts as a molecular adaptor for ARID3C nuclear import. This is consistent with NPM1 broader role as a nucleocytoplasmic shuttling chaperone for multiple cargo proteins.
    supported_by:
    - reference_id: PMID:38231884
      supporting_text: >-
        Mutating this binding site prevented ARID3C from interacting with NPM1, resulting
        in its retention in the cytoplasm instead of translocation to the nucleus.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9725009
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-9725009). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9725023
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-9725023). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9725030
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-9725030). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9851090
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-9851090). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700181
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700181). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700190
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700190). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700193
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700193). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9710914
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9710914). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9710917
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9710917). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712078
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712078). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712079
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712079). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712081
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712081). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712082
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712082). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712083
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712083). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712084
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712084). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712085
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712085). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712086
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712086). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712087
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712087). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9712088
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9712088). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9724099
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9724099). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9725009
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9725009). NPM1 shuttles to the cytoplasm/cytosol as part of its normal function in ribosome export and protein transport.
    action: ACCEPT
    reason: >-
      Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling function.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9850958
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9850958). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0019843
    label: rRNA binding
  evidence_type: IPI
  original_reference_id: PMID:24106084
  review:
    summary: >-
      PMID:24106084 demonstrated that NPM1/B23 RNA binding activity is essential for ribosome biogenesis, with the C-terminal domain and intrinsically disordered basic region mediating RNA binding. The basic IDR alone strongly binds to RNA.
    action: ACCEPT
    reason: >-
      rRNA binding is a core molecular function of NPM1. Directly demonstrated in PMID:24106084.
    supported_by:
    - reference_id: PMID:24106084
      supporting_text: >-
        Nucleophosmin (NPM1/B23) is a nucleolar protein implicated in growth-associated
        functions, in which the RNA binding activity of B23 plays essential roles in
        ribosome biogenesis.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:24106084
  review:
    summary: >-
      PMID:24106084 showed NPM1 forms homo-oligomers (pentamers/decamers) through inter-molecular interactions of its IDRs. The N-terminal domain mediates oligomerization.
    action: ACCEPT
    reason: >-
      NPM1 forms pentamers and decamers through homooligomerization. This is a fundamental property confirmed by crystal structure (PDB:2P1B) and multiple biochemical studies.
    supported_by:
    - reference_id: PMID:24106084
      supporting_text: >-
        Chemical cross-linking experiments and fluorescent labeling of bipartite
        tetracysteine-tagged proteins suggested that the inter- and intra-molecular
        interactions between the two IDRs contribute to the regulation of the RNA binding
        activity of CTD to control the cellular localization and functions of B23.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23972994
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:23972994 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0090398
    label: cellular senescence
  evidence_type: IMP
  original_reference_id: PMID:12080348
  review:
    summary: >-
      PMID:12080348 showed NPM1 regulates p53 stability and transcriptional activity. NPM1 overexpression suppressed cell growth. The connection to senescence is through p53 regulation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cellular senescence is a downstream phenotypic consequence of NPM1 effects on p53 stabilization. Not a core molecular function but a pleiotropic effect.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4086088
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-4086088). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4086059
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-4086059). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25956029
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:25956029 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700131
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700131). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700179
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9700179). This annotation relates to the NPM1-ALK fusion oncoprotein signaling pathway in anaplastic large cell lymphoma. The cytosol localization reflects the ALK fusion context, not normal NPM1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosol localization in this context is specific to the NPM1-ALK fusion oncoprotein. Not relevant to normal NPM1 function but reflects a real disease-associated biology.
- term:
    id: GO:1990904
    label: ribonucleoprotein complex
  evidence_type: IDA
  original_reference_id: PMID:18809582
  review:
    summary: >-
      IDA annotation from PMID:18809582 which demonstrated NPM1 serves as a rate-limiting nuclear export chaperone for the mammalian ribosome. NPM1 was found associated with ribonucleoprotein complexes.
    action: ACCEPT
    reason: >-
      NPM1 associates with ribonucleoprotein complexes as part of its core ribosome biogenesis and export function. Directly demonstrated.
    supported_by:
    - reference_id: PMID:18809582
      supporting_text: >-
        Nucleophosmin serves as a rate-limiting nuclear export chaperone for the
        Mammalian ribosome.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:19208757
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:19208757. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:1902629
    label: regulation of mRNA stability involved in cellular response to UV
  evidence_type: IMP
  original_reference_id: PMID:12080348
  review:
    summary: >-
      PMID:12080348 primarily demonstrated NPM1 regulation of p53 stability and transcriptional activity. The connection to mRNA stability in UV response seems tenuous for this reference.
    action: UNDECIDED
    reason: >-
      The specific mechanism by which NPM1 regulates mRNA stability in UV response is not clearly demonstrated in PMID:12080348. Need to verify this annotation against the primary data.
- term:
    id: GO:0001652
    label: granular component
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9727886
  review:
    summary: >-
      TAS annotation for granular component from Reactome (SARS-CoV-1 N protein binds NPM1). NPM1 localizes to the GC of the nucleolus. This Reactome entry is about viral interaction but the localization is correct.
    action: ACCEPT
    reason: >-
      NPM1 localizes to the granular component of the nucleolus. Correct localization, consistent with IEA annotation and UniProt.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-180728
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-180728). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-180736
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-180736). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-606287
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-606287). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-606289
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-606289). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-606326
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-606326). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869542
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-8869542). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869543
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-8869543). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869549
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-8869549). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869568
  review:
    summary: >-
      TAS annotation for nucleoplasm from Reactome (Reactome:R-HSA-8869568). NPM1 nucleoplasm localization is well-established. Redundant with IBA and multiple IDA annotations.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is correct for NPM1. Redundant but consistent with existing evidence.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:25956029
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:25956029. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:25956029
  review:
    summary: >-
      PMID:25956029 showed NPM1 in complex with MYC enhances transcription of MYC target genes. NOP53 acts as upstream negative regulator by competing with MYC for NPM1 binding.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transcription coactivation is a non-core pleiotropic function. Redundant with IBA annotation.
    supported_by:
    - reference_id: PMID:25956029
      supporting_text: >-
        The nucleolar protein GLTSCR2 is an upstream negative regulator of the oncogenic
        Nucleophosmin-MYC axis.
- term:
    id: GO:0001046
    label: core promoter sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:19160485
  review:
    summary: >-
      PMID:19160485 studied the L23-NPM1-Miz1 circuit. NPM1 was shown to be present at core promoters in complex with Miz1. However, NPM1 DNA binding may be indirect through the complex.
    action: UNDECIDED
    reason: >-
      NPM1 is primarily known as a histone/RNA chaperone, not a DNA-binding protein per se. Its presence at promoters may be through protein complexes rather than direct DNA sequence-specific binding. Need more evidence to confirm direct DNA binding.
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IDA
  original_reference_id: PMID:19160485
  review:
    summary: >-
      PMID:19160485 showed NPM1 coordinates Miz1 function with cell growth through the L23-NPM1-Miz1 circuit. NPM1 acts as a coactivator in this context.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transcription coactivator activity is a non-core function of NPM1. It is documented but secondary to histone chaperoning and ribosome biogenesis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19160485
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:19160485 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: PMID:19160485
  review:
    summary: >-
      IDA annotation for nucleoplasm from PMID:19160485, which studied the ribosomal protein L23-NPM1 circuit coordinating Miz1 function with cell growth. NPM1 was shown in the nucleoplasm in this context.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is well-established for NPM1. Consistent with multiple other evidence.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:19160485
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:19160485. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:19160485
  review:
    summary: >-
      IDA annotation for protein-containing complex from PMID:19160485. NPM1 forms complexes with many proteins including the L23-Miz1 complex.
    action: ACCEPT
    reason: >-
      NPM1 exists in multiple protein complexes (pentamer/decamer, ribosomal complexes, transcription complexes). This is a general but correct localization term.
- term:
    id: GO:0032993
    label: protein-DNA complex
  evidence_type: IDA
  original_reference_id: PMID:19160485
  review:
    summary: >-
      IDA annotation for protein-DNA complex. PMID:19160485 showed NPM1 is found in protein-DNA complexes at promoters in the L23-Miz1 circuit.
    action: KEEP_AS_NON_CORE
    reason: >-
      NPM1 association with protein-DNA complexes is context-dependent and related to its transcription coactivator function, not a core activity.
- term:
    id: GO:0034644
    label: cellular response to UV
  evidence_type: IDA
  original_reference_id: PMID:19160485
  review:
    summary: >-
      PMID:19160485 showed NPM1 role in cellular response to UV through the L23-NPM1-Miz1 pathway. Under UV stress, ribosomal stress releases L23 which disrupts NPM1-Miz1 complex.
    action: KEEP_AS_NON_CORE
    reason: >-
      UV response involvement is a stress-related function secondary to NPM1 core roles. NPM1 translocates from nucleolus under stress conditions.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:19160485
  review:
    summary: >-
      IDA annotation for positive regulation of transcription from PMID:19160485 studying L23-NPM1-Miz1 circuit. Redundant with other transcription coactivation annotations.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transcription coactivation is a non-core function. Redundant with IBA annotation already reviewed.
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:19160485
  review:
    summary: >-
      PMID:19160485 showed NPM1 interacts with Miz1 transcription factor. NPM1 also interacts with AP2alpha (PMID:17318229), NF-kappaB (PMID:15087454), and MYC (PMID:25956029).
    action: ACCEPT
    reason: >-
      NPM1 binds multiple transcription factors as part of its coactivator/corepressor function. This is more specific than protein binding and captures a real molecular function.
    supported_by:
    - reference_id: PMID:17318229
      supporting_text: >-
        Nucleophosmin (NPM) is an important nucleolar phosphoprotein with pleiotropic
        functions in various cellular processes.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6801675
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-6801675). NPM1 shuttles to the cytoplasm/cytosol as part of its normal function in ribosome export and protein transport.
    action: ACCEPT
    reason: >-
      Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23019224
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:23019224 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22528486
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:22528486 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:22528486
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:22528486. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:22528486
  review:
    summary: >-
      PMID:22528486 showed NPM1 antagonizes ATF5 inhibitory effect on cell proliferation and promotes ATF5 degradation in hepatocellular carcinoma cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell proliferation promotion through ATF5 degradation is a context-specific pleiotropic effect, not a core molecular function.
    supported_by:
    - reference_id: PMID:22528486
      supporting_text: >-
        NPM1-promoted ATF5 down-regulation diminished ATF5-mediated repression of
        cAMP-responsive element-dependent gene transcription and abrogates ATF5-induced
        G(2)/M cell cycle blockade and inhibition of cell proliferation in HCC cells.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:22528486
  review:
    summary: >-
      PMID:22528486 showed NPM1 promotes ATF5 degradation, relieving ATF5-mediated transcriptional repression. This is an indirect transcription regulation effect.
    action: KEEP_AS_NON_CORE
    reason: >-
      Positive transcription regulation through ATF5 degradation is indirect. Not a core function.
- term:
    id: GO:1902751
    label: positive regulation of cell cycle G2/M phase transition
  evidence_type: IDA
  original_reference_id: PMID:22528486
  review:
    summary: >-
      PMID:22528486 showed NPM1 relieves ATF5-induced G2/M blockade through ATF5 degradation.
    action: KEEP_AS_NON_CORE
    reason: >-
      G2/M transition regulation is an indirect consequence of ATF5 degradation by NPM1. Not a core function.
    supported_by:
    - reference_id: PMID:22528486
      supporting_text: >-
        NPM1 interaction with ATF5 displaces HSP70, a known ATF5-interacting protein,
        from ATF5 protein complexes and antagonizes its role in stabilization of ATF5 protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20075868
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:20075868 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: HDA
  original_reference_id: PMID:21423176
  review:
    summary: >-
      HDA annotation for focal adhesion from a high-throughput proteomics study of myosin-II-responsive focal adhesion proteome. NPM1 is primarily nucleolar, not known to have focal adhesion functions.
    action: REMOVE
    reason: >-
      Focal adhesion localization is likely an artifact of the high-throughput proteomics approach. NPM1 is a nucleolar protein with no established role in focal adhesions.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: >-
      HDA annotation for membrane from a high-throughput study defining the membrane proteome of NK cells. NPM1 is not a membrane protein.
    action: REMOVE
    reason: >-
      Membrane localization is likely a contaminant in the high-throughput proteomics screen. NPM1 is a nucleolar/nuclear protein with no transmembrane domain or membrane association.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22720776
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:22720776 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:22720776
  review:
    summary: >-
      IDA annotation for nucleus from PMID:22720776 (PHF6 interacts with NuRD complex). NPM1 is well-established as a nuclear protein.
    action: ACCEPT
    reason: >-
      Nuclear localization is fundamental to NPM1. Consistent with all other evidence.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  review:
    summary: >-
      HDA annotation for nucleus from PMID:21630459 (proteomic characterization of human sperm nucleus). NPM1 is a nuclear protein.
    action: ACCEPT
    reason: >-
      Nuclear localization is correct for NPM1. Consistent with all other evidence.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  review:
    summary: >-
      HDA annotation for RNA binding from PMID:22658674 (atlas of mammalian mRNA-binding proteins). NPM1 binds RNA including mRNA and rRNA.
    action: ACCEPT
    reason: >-
      RNA binding is a core function of NPM1. Consistent with IBA and IDA evidence.
    supported_by:
    - reference_id: PMID:22658674
      supporting_text: >-
        Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  review:
    summary: >-
      HDA annotation for RNA binding from PMID:22681889 (mRNA-bound proteome study). NPM1 was identified as an mRNA-binding protein.
    action: ACCEPT
    reason: >-
      RNA binding is a core function of NPM1. Consistent with extensive evidence.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12882984
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:12882984 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:12882984
  review:
    summary: >-
      PMID:12882984 showed NPM1 overexpression inhibited apoptosis through PKR inhibition. Enforced NPM expression in FA lymphoblasts reduced aberrant apoptotic responses.
    action: KEEP_AS_NON_CORE
    reason: >-
      Anti-apoptotic function through PKR inhibition is well-demonstrated but is a secondary pleiotropic effect, not a core molecular function.
    supported_by:
    - reference_id: PMID:12882984
      supporting_text: >-
        Overexpression of NPM suppressed PKR activity, enhanced protein synthesis, and
        inhibited apoptosis.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-180725
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-180725). NPM1 shuttles to the cytoplasm/cytosol as part of its normal function in ribosome export and protein transport.
    action: ACCEPT
    reason: >-
      Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling function.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835328
  review:
    summary: >-
      TAS annotation for cytosol from Reactome (Reactome:R-HSA-9835328). NPM1 shuttles to the cytoplasm/cytosol as part of its normal function in ribosome export and protein transport.
    action: ACCEPT
    reason: >-
      Cytosol localization is consistent with NPM1 nucleocytoplasmic shuttling function.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:20352051
  review:
    summary: >-
      PMID:20352051 showed NPM1 directly interacts with PLK2 in a Polo-box dependent manner. PLK2 phosphorylates NPM1 at Ser4 to trigger centriole duplication.
    action: ACCEPT
    reason: >-
      NPM1 binds protein kinases PLK2, CDK2/cyclin E, ROCK2, and Aurora kinases as part of its regulatory roles. More specific than protein binding.
    supported_by:
    - reference_id: PMID:20352051
      supporting_text: >-
        We find that Plk2 and NPM/B23 interact in vitro in a Polo-box dependent manner.
        An association between both proteins was also observed in vivo.
- term:
    id: GO:0046599
    label: regulation of centriole replication
  evidence_type: IMP
  original_reference_id: PMID:20352051
  review:
    summary: >-
      PMID:20352051 demonstrated PLK2 phosphorylation of NPM1 at Ser4 triggers centriole duplication. Non-phosphorylatable S4A mutant interfered with centriole reduplication.
    action: ACCEPT
    reason: >-
      Regulation of centriole replication is a core function of NPM1, demonstrated through phospho-mutant analysis.
    supported_by:
    - reference_id: PMID:20352051
      supporting_text: >-
        Notably, expression of a non-phosphorylatable NPM/B23 S4A mutant interferes with
        centriole reduplication in S-phase arrested cells and leads to a dilution of
        centriole numbers in unperturbed U2OS cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17015463
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:17015463 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:18809582
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:18809582. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IDA
  original_reference_id: PMID:19188445
  review:
    summary: >-
      PMID:19188445 showed NPM1 interacts with APEX1/Ref-1 in nucleoli and plays a role in rRNA quality control. NPM1 stimulates APEX1 endonuclease activity on AP double-stranded DNA. This represents a role in DNA repair within the rDNA context.
    action: KEEP_AS_NON_CORE
    reason: >-
      DNA repair involvement is secondary to NPM1 core nucleolar function. The role is specifically in rRNA quality control through APEX1 regulation.
    supported_by:
    - reference_id: PMID:19188445
      supporting_text: >-
        APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in the rRNA
        quality control process.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19188445
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:19188445 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:19188445
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:19188445. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20159986
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:20159986 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19410545
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:19410545 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0043023
    label: ribosomal large subunit binding
  evidence_type: IDA
  original_reference_id: PMID:18809582
  review:
    summary: >-
      PMID:18809582 directly demonstrated NPM1 binds the large ribosomal subunit as part of its rate-limiting nuclear export chaperone function.
    action: ACCEPT
    reason: >-
      Large ribosomal subunit binding is a core molecular function of NPM1. Directly demonstrated.
    supported_by:
    - reference_id: PMID:18809582
      supporting_text: >-
        Nucleophosmin serves as a rate-limiting nuclear export chaperone for the
        Mammalian ribosome.
- term:
    id: GO:0043024
    label: ribosomal small subunit binding
  evidence_type: IDA
  original_reference_id: PMID:18809582
  review:
    summary: >-
      PMID:18809582 demonstrated NPM1 binds both large and small ribosomal subunits.
    action: ACCEPT
    reason: >-
      Small ribosomal subunit binding is a core molecular function of NPM1. Directly demonstrated.
    supported_by:
    - reference_id: PMID:18809582
      supporting_text: >-
        Nucleophosmin serves as a rate-limiting nuclear export chaperone for the
        Mammalian ribosome.
- term:
    id: GO:0010826
    label: negative regulation of centrosome duplication
  evidence_type: IMP
  original_reference_id: PMID:16041368
  review:
    summary: >-
      PMID:16041368 showed Ran-Crm1 controls NPM1 association with centrosomes. NPM1 acts as a negative regulator - its presence on unduplicated centrosomes prevents duplication until it is phosphorylated and released.
    action: ACCEPT
    reason: >-
      Negative regulation of centrosome duplication is a core function of NPM1. NPM1 licensing of centrosome duplication through its phosphorylation-dependent dissociation.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IDA
  original_reference_id: PMID:12058066
  review:
    summary: >-
      IDA annotation for RNA binding from PMID:12058066 which showed RNA binding activity of B23 is modulated by phosphorylation with cell cycle-dependent kinase.
    action: ACCEPT
    reason: >-
      RNA binding is a core function of NPM1. Directly demonstrated by IDA.
    supported_by:
    - reference_id: PMID:12058066
      supporting_text: >-
        It has been shown that B23 binds to nucleic acids, digests RNA, and is localized in
        nucleolar granular components from which preribosomal particles are transported to
        cytoplasm.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: PMID:12058066
  review:
    summary: >-
      IDA annotation for nucleoplasm from PMID:12058066. NPM1 is found in the nucleoplasm particularly when phosphorylated. Consistent with other evidence.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is well-established. Consistent with other evidence.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:16041368
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:16041368. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:0006913
    label: nucleocytoplasmic transport
  evidence_type: IDA
  original_reference_id: PMID:16041368
  review:
    summary: >-
      IDA annotation for nucleocytoplasmic transport from PMID:16041368 showing Ran-Crm1 controls NPM1 shuttling for centrosome duplication regulation.
    action: ACCEPT
    reason: >-
      Nucleocytoplasmic transport is a core function of NPM1, regulated by Ran-Crm1 pathway.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: NAS
  original_reference_id: PMID:16130169
  review:
    summary: >-
      NAS annotation for signal transduction from PMID:16130169 (proteomics of etoposide-induced apoptosis in endothelial cells). Very broad term. NPM1 has indirect roles in signaling through p53, ARF, and PKR pathways.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Signal transduction is far too broad for NPM1. Its signaling roles are indirect, through specific pathways (p53, PKR inhibition). The NAS evidence from a proteomics study is weak.
- term:
    id: GO:0031616
    label: spindle pole centrosome
  evidence_type: IDA
  original_reference_id: PMID:16041368
  review:
    summary: >-
      IDA annotation for spindle pole centrosome from PMID:16041368 which showed NPM1 associates with centrosomes during mitosis, controlled by Ran-Crm1.
    action: ACCEPT
    reason: >-
      NPM1 localizes to spindle pole centrosomes during mitosis. Consistent with its centrosome cycle regulation function.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: NAS
  original_reference_id: PMID:16130169
  review:
    summary: >-
      NAS annotation for negative regulation of apoptosis from PMID:16130169 (proteomics study). NPM1 anti-apoptotic activity is better supported by PMID:12882984 (PKR inhibition).
    action: KEEP_AS_NON_CORE
    reason: >-
      Anti-apoptotic function is a secondary pleiotropic effect. Better supported by other evidence. NAS from proteomics is weak but the function is real.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16648475
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:16648475 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0006334
    label: nucleosome assembly
  evidence_type: IDA
  original_reference_id: PMID:11602260
  review:
    summary: >-
      PMID:11602260 directly demonstrated NPM1 mediates nucleosome assembly and decondenses sperm chromatin. This is a histone chaperone function.
    action: ACCEPT
    reason: >-
      Nucleosome assembly is a core function of NPM1 as a histone chaperone. Directly demonstrated.
    supported_by:
    - reference_id: PMID:11602260
      supporting_text: >-
        Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3,
        to mediate formation of nucleosome, and to decondense sperm chromatin.
- term:
    id: GO:0042393
    label: histone binding
  evidence_type: IDA
  original_reference_id: PMID:11602260
  review:
    summary: >-
      IDA annotation for histone binding from PMID:11602260. NPM1 binds core histones H3, H2B, and H4. Consistent with IBA annotation already accepted.
    action: ACCEPT
    reason: >-
      Histone binding is a core molecular function of NPM1. Directly demonstrated.
    supported_by:
    - reference_id: PMID:11602260
      supporting_text: >-
        Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3,
        to mediate formation of nucleosome, and to decondense sperm chromatin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18420587
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:18420587 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0008104
    label: intracellular protein localization
  evidence_type: IDA
  original_reference_id: PMID:18420587
  review:
    summary: >-
      PMID:18420587 showed NPM1 selectively stores and protects ribosomal protein S9 in nucleoli, facilitating ribosome biogenesis.
    action: ACCEPT
    reason: >-
      NPM1 controls intracellular localization of ribosomal proteins and other cargo. This is part of its core chaperoning function.
    supported_by:
    - reference_id: PMID:18420587
      supporting_text: >-
        Our results suggest that B23 selectively stores, and protects ribosomal protein S9
        in nucleoli and therefore could facilitate ribosome biogenesis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17475909
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:17475909 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:17475909
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:17475909. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17438371
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:17438371 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:11420665
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:11420665. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15184379
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:15184379 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0030957
    label: Tat protein binding
  evidence_type: IDA
  original_reference_id: PMID:9094689
  review:
    summary: >-
      PMID:9094689 showed NPM1/B23 binds HIV Tat protein and is necessary for its nucleolar localization. This is a host-virus interaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      HIV Tat binding is a specific host-virus interaction, not a core function of NPM1. However, it reflects NPM1 general role as a nucleolar shuttle protein.
    supported_by:
    - reference_id: PMID:9094689
      supporting_text: >-
        Nucleolar shuttle protein B23 was found to bind to human immunodeficiency virus
        protein Tat, and this binding required the nucleolar localization motif of Tat.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:10211837
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962).
      The annotation is based on PMID:10211837 (Szebeni & Olson, 1999), which demonstrated
      that NPM1/B23 has genuine molecular chaperone activities including both holdase
      (anti-aggregation) and foldase (refolding) functions using multiple protein substrates.
      B23 inhibited aggregation of HIV-1 Rev protein, protected LADH, carboxypeptidase A,
      citrate synthase, and rhodanese from thermal aggregation, preserved LADH enzyme activity
      during heat stress, and promoted restoration of LADH activity after guanidine-HCl
      denaturation. It preferentially bound denatured substrates and exposed hydrophobic
      regions when complexed with denatured proteins. The demonstrated refolding activity
      (foldase function) best maps to GO:0044183 (protein folding chaperone). UniProt also
      classifies NPM1 with the keyword "Chaperone" and describes it as acting "as a
      chaperonin for the core histones H3, H2B and H4" (citing PMID:16107701). The histone
      chaperone activity is separately supported by PMID:11602260, which showed NPM1 binds
      histones (preferentially H3), mediates nucleosome formation, and decondenses sperm
      chromatin, and is better captured by GO:0140713 (histone chaperone activity). Since
      the evidence in PMID:10211837 specifically demonstrates protein folding chaperone
      activity (not just binding to unfolded proteins), MODIFY to GO:0044183 is appropriate.
    action: MODIFY
    reason: >-
      GO:0051082 is scheduled for obsolescence (go-ontology#30962). The obsoletion notice
      specifies that annotations should be redirected to either GO:0044183 (protein folding
      chaperone, i.e. foldase) or to a holdase chaperone term. PMID:10211837 demonstrates
      that NPM1 has both holdase activity (preventing aggregation of multiple substrates)
      and foldase activity (promoting restoration of LADH activity after guanidine-HCl
      denaturation). Since GO:0044183 captures the foldase/refolding function and NPM1
      clearly promotes refolding, this is the most appropriate replacement. Additionally,
      the histone chaperone function of NPM1 (PMID:11602260, PMID:16107701) is a distinct
      activity best captured by GO:0140713, which should be proposed as a NEW annotation.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:11602260
    - PMID:16107701
    supported_by:
    - reference_id: PMID:10211837
      supporting_text: >-
        Protein B23 inhibited the aggregation of the Rev protein, with the amount of
        inhibition proportional to the concentration of B23 added. This activity was
        saturable with nearly complete inhibition when the molar ratio of B23:Rev was
        slightly above one.
    - reference_id: PMID:10211837
      supporting_text: >-
        Protein B23 also protected liver alcohol dehydrogenase (LADH), carboxypeptidase A,
        citrate synthase, and rhodanese from aggregation during thermal denaturation and
        preserved the enzyme activity of LADH under these conditions.
    - reference_id: PMID:10211837
      supporting_text: >-
        In addition, protein B23 was able to promote the restoration of activity of LADH
        previously denatured with guanidine-HCl.
    - reference_id: PMID:10211837
      supporting_text: >-
        Protein B23 preferentially bound denatured substrates and exposed hydrophobic
        regions when complexed with denatured proteins. Thus, by several criteria, protein
        B23 behaves like a molecular chaperone; these activities may be related to its
        role in ribosome biogenesis.
    - reference_id: PMID:11602260
      supporting_text: >-
        Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3,
        to mediate formation of nucleosome, and to decondense sperm chromatin. These
        activities of B23 were dependent on its acidic regions as other histone chaperones,
        suggesting that B23/nucleophosmin is a member of histone chaperone proteins.
- term:
    id: GO:0051059
    label: NF-kappaB binding
  evidence_type: IDA
  original_reference_id: PMID:15087454
  review:
    summary: >-
      PMID:15087454 demonstrated physical interaction between NPM and NF-kappaB using co-immunoprecipitation and NF-kappaB affinity chromatography. NPM was the most abundant protein in the NF-kappaB-bound fraction.
    action: KEEP_AS_NON_CORE
    reason: >-
      NF-kappaB binding is demonstrated but is part of NPM1 non-core transcription coactivator function. Not a core molecular function.
    supported_by:
    - reference_id: PMID:15087454
      supporting_text: >-
        Co-immunoprecipitation studies suggest a physical interaction between NPM and
        NF-kappaB proteins.
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IDA
  original_reference_id: PMID:15087454
  review:
    summary: >-
      PMID:15087454 showed NPM1 acts as NF-kappaB coactivator for SOD2 induction. Increasing NPM expression increased SOD2 transcription dose-dependently.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transcription coactivator activity is a non-core function. Redundant with annotation from PMID:19160485.
    supported_by:
    - reference_id: PMID:15087454
      supporting_text: >-
        The results indicate that an increase NPM expression leads to increased MnSOD gene
        transcription in a dose-dependent manner.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:11051553
  review:
    summary: >-
      PMID:11051553 showed NPM1 associates specifically with unduplicated centrosomes and dissociates upon CDK2/cyclin E phosphorylation to initiate centrosome duplication.
    action: ACCEPT
    reason: >-
      Centrosome localization is a core feature of NPM1, directly demonstrated by IDA in a landmark study.
    supported_by:
    - reference_id: PMID:11051553
      supporting_text: >-
        NPM/B23 associates specifically with unduplicated centrosomes, and NPM/B23
        dissociates from centrosomes by CDK2/cyclin E-mediated phosphorylation.
- term:
    id: GO:0007098
    label: centrosome cycle
  evidence_type: IMP
  original_reference_id: PMID:11051553
  review:
    summary: >-
      PMID:11051553 demonstrated NPM1 is a CDK2/cyclin E substrate in centrosome duplication. NPM1 phosphorylation triggers centrosome duplication initiation.
    action: ACCEPT
    reason: >-
      Centrosome cycle regulation is a core function of NPM1. Landmark study demonstrating direct involvement.
    supported_by:
    - reference_id: PMID:11051553
      supporting_text: >-
        We identified nucleophosmin (NPM/B23) as a substrate of CDK2/cyclin E in
        centrosome duplication.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12080348
  review:
    summary: >-
      Protein binding (GO:0005515) is uninformative and does not capture the specific
      molecular function of the interaction. NPM1 interacts with many proteins as part of
      its diverse functions. This annotation from PMID:12080348 should be replaced with more
      specific MF terms.
    action: REMOVE
    reason: >-
      Per curation guidelines, protein binding is too vague to be informative. More specific
      molecular function terms (e.g. histone chaperone activity, protein folding chaperone,
      ribosomal subunit binding) better capture NPM1 activities.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:12080348
  review:
    summary: >-
      IDA annotation for nucleus from PMID:12080348 which studied NPM1 regulation of p53. NPM1 is a nuclear protein. Consistent with all other evidence.
    action: ACCEPT
    reason: >-
      Nuclear localization is fundamental to NPM1 function. Well-established.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: PMID:12080348
  review:
    summary: >-
      IDA annotation for nucleolus from PMID:12080348. NPM1 is one of the most abundant nucleolar proteins. Its nucleolar localization is a core feature.
    action: ACCEPT
    reason: >-
      Nucleolus is the primary localization of NPM1. Well-established across many independent studies.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:9121481
  review:
    summary: >-
      IDA annotation for cytoplasm from PMID:9121481 which studied the NPM-ALK fusion oncogene. NPM1 was shown to shuttle between nucleus and cytoplasm.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization confirmed by IDA. NPM1 is a nucleocytoplasmic shuttling protein.
    supported_by:
    - reference_id: PMID:9121481
      supporting_text: >-
        Cell fractionation studies of the t(2;5) translocation-containing lymphoma cell
        line SUP-M2 showed NPM-ALK to be localized within both the cytoplasmic and nuclear
        compartments.
- term:
    id: GO:0006886
    label: intracellular protein transport
  evidence_type: TAS
  original_reference_id: PMID:12080348
  review:
    summary: >-
      TAS annotation for intracellular protein transport. NPM1 functions as a nucleocytoplasmic shuttle for ribosomal subunits and other cargo proteins. PMID:12080348 discusses NPM1 shuttling.
    action: ACCEPT
    reason: >-
      Intracellular protein transport is a core function of NPM1. It acts as a nuclear export chaperone for ribosomes and import adaptor for various proteins.
- term:
    id: GO:0006913
    label: nucleocytoplasmic transport
  evidence_type: TAS
  original_reference_id: PMID:12080348
  review:
    summary: >-
      TAS annotation for nucleocytoplasmic transport from PMID:12080348. NPM1 is a well-established nucleocytoplasmic shuttling protein.
    action: ACCEPT
    reason: >-
      Nucleocytoplasmic transport is a core function of NPM1. It shuttles between nucleus and cytoplasm to export ribosomal subunits.
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:12080348
  review:
    summary: >-
      PMID:12080348 showed NPM1 stabilizes p53 and can suppress cell growth. However, NPM1 also has pro-proliferative roles through ribosome biogenesis and ATF5 degradation. The negative regulation may reflect specific contexts.
    action: KEEP_AS_NON_CORE
    reason: >-
      NPM1 has context-dependent effects on proliferation. The negative regulation is through p53 stabilization in certain conditions. Not a core defining function.
- term:
    id: GO:0042255
    label: ribosome assembly
  evidence_type: TAS
  original_reference_id: PMID:12080348
  review:
    summary: >-
      TAS annotation for ribosome assembly. NPM1 is essential for ribosome biogenesis including assembly, processing, and export (PMID:18809582, PMID:16648475).
    action: ACCEPT
    reason: >-
      Ribosome assembly is a core function of NPM1. Well-supported by multiple direct studies.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:9121481
  review:
    summary: >-
      IDA annotation for protein homodimerization from PMID:9121481. NPM1 forms pentamers and decamers. Consistent with IPI from PMID:24106084 and structural data.
    action: ACCEPT
    reason: >-
      NPM1 oligomerization is a fundamental structural property. Forms pentamers/decamers essential for function.
- term:
    id: GO:0140713
    label: histone chaperone activity
  evidence_type: IDA
  original_reference_id: PMID:11602260
  review:
    summary: >-
      NPM1 functions as a histone chaperone for core histones H3, H2B, and H4. PMID:11602260
      demonstrated NPM1 binds histones (preferentially H3), mediates nucleosome formation,
      and decondenses sperm chromatin. These activities depend on its acidic regions, as in
      other histone chaperones. PMID:16107701 showed NPM1 enhances acetylation-dependent
      chromatin transcription, disrupting nucleosomal structure. UniProt classifies NPM1 as
      a chaperonin for core histones. GO:0140713 (histone chaperone activity) is the
      appropriate specific term for this well-documented function that is not currently
      annotated with this precise GO term.
    action: NEW
    reason: >-
      Histone chaperone activity is a core molecular function of NPM1 that is well-supported
      by multiple experimental studies but is not captured by any existing annotation at
      this level of specificity. The existing annotations cover histone binding (GO:0042393)
      and chromatin remodeling (GO:0006338) but not the specific chaperone activity.
    supported_by:
    - reference_id: PMID:11602260
      supporting_text: >-
        Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3,
        to mediate formation of nucleosome, and to decondense sperm chromatin. These
        activities of B23 were dependent on its acidic regions as other histone chaperones,
        suggesting that B23/nucleophosmin is a member of histone chaperone proteins.
    - reference_id: PMID:16107701
      supporting_text: >-
        Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin
        transcription.
core_functions:
- molecular_function:
    id: GO:0140713
    label: histone chaperone activity
  description: >-
    NPM1 functions as a histone chaperone for core histones H3, H2B, and H4, binding them
    through its acidic intrinsically disordered regions whose charge patterning mimics DNA.
    It mediates nucleosome assembly and disassembly, decondenses sperm chromatin, and enhances
    acetylation-dependent chromatin transcription by disrupting nucleosomal structure. This is
    an ATP-independent chaperone activity distinct from its general protein folding chaperone
    function. Histone chaperoning is a primary molecular activity of NPM1 in the nucleus, and
    is modulated by post-translational modifications including phosphorylation, acetylation,
    and SUMOylation (DOI:10.3390/cells13151266).
  directly_involved_in:
    - id: GO:0006334
      label: nucleosome assembly
    - id: GO:0006338
      label: chromatin remodeling
  locations:
    - id: GO:0005730
      label: nucleolus
    - id: GO:0005654
      label: nucleoplasm
  supported_by:
    - reference_id: PMID:11602260
      supporting_text: >-
        Nucleophosmin/B23 was shown to bind to histones, preferentially to histone H3, to
        mediate formation of nucleosome, and to decondense sperm chromatin. These activities
        of B23 were dependent on its acidic regions as other histone chaperones, suggesting
        that B23/nucleophosmin is a member of histone chaperone proteins.
    - reference_id: PMID:16107701
      supporting_text: >-
        Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin
        transcription. Presumably, nucleophosmin disrupts the nucleosomal structure in an
        acetylation-dependent manner, resulting in the transcriptional activation.
- molecular_function:
    id: GO:0140142
    label: nucleocytoplasmic carrier activity
  description: >-
    NPM1 is a rate-limiting nucleocytoplasmic shuttling chaperone that directly binds both
    large and small ribosomal subunits and mediates their CRM1/XPO1-dependent nuclear export.
    It associates with maturing nuclear 60S ribosomal subunits via ribosomal protein L5
    and delivers them to the cytoplasm for assembly into functional 80S ribosomes and
    polysomes. NPM1 also acts as a nuclear import adaptor, shuttling cargo proteins such
    as ARID3C and HIV-1 Tat to the nucleolus. The Ran-Crm1 pathway controls NPM1
    nucleocytoplasmic distribution. Within the nucleolus, NPM1 is a major driver of
    liquid-liquid phase separation (LLPS) in the granular component (GC), forming
    condensate droplets with arginine-rich proteins and rRNA that scaffold pre-ribosomal
    particle maturation. Oligomer stability, regulated by phosphorylation at sites such as
    Ser125, directly controls droplet fluidity and thus nucleolar dynamics
    (DOI:10.1101/2023.01.23.525122). This transport activity integrates NPM1 roles in
    nucleolar ribosome assembly with cytoplasmic ribosome delivery.
  directly_involved_in:
    - id: GO:0000055
      label: ribosomal large subunit export from nucleus
    - id: GO:0000056
      label: ribosomal small subunit export from nucleus
    - id: GO:0042273
      label: ribosomal large subunit biogenesis
    - id: GO:0042274
      label: ribosomal small subunit biogenesis
    - id: GO:0006913
      label: nucleocytoplasmic transport
  locations:
    - id: GO:0005730
      label: nucleolus
    - id: GO:0001652
      label: granular component
    - id: GO:0005737
      label: cytoplasm
  supported_by:
    - reference_id: PMID:18809582
      supporting_text: >-
        Nucleophosmin serves as a rate-limiting nuclear export chaperone for the
        Mammalian ribosome.
    - reference_id: PMID:16648475
      supporting_text: >-
        Direct interaction of NPM with rpL5 mediated the colocalization of NPM with
        maturing nuclear 60S ribosomal subunits, as well as newly exported and assembled
        80S ribosomes and polysomes.
    - reference_id: PMID:18420587
      supporting_text: >-
        Our results suggest that B23 selectively stores, and protects ribosomal protein S9
        in nucleoli and therefore could facilitate ribosome biogenesis.
- molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  description: >-
    NPM1 exhibits general molecular chaperone activity independent of its histone chaperone
    function. It preferentially binds denatured protein substrates and prevents their
    aggregation (holdase activity), exposes hydrophobic regions when complexed with denatured
    proteins, and promotes restoration of enzyme activity after denaturation (foldase
    activity). This chaperone function is likely related to its roles in ribosome biogenesis
    where it assists in folding and protecting ribosomal proteins during assembly, including
    selective storage and protection of ribosomal protein S9 in the nucleolus.
  directly_involved_in:
    - id: GO:0042254
      label: ribosome biogenesis
    - id: GO:0006457
      label: protein folding
  locations:
    - id: GO:0005730
      label: nucleolus
  supported_by:
    - reference_id: PMID:10211837
      supporting_text: >-
        Protein B23 preferentially bound denatured substrates and exposed hydrophobic
        regions when complexed with denatured proteins. Protein B23 also protected liver
        alcohol dehydrogenase (LADH), carboxypeptidase A, citrate synthase, and rhodanese
        from aggregation during thermal denaturation. In addition, protein B23 was able
        to promote the restoration of activity of LADH previously denatured with
        guanidine-HCl.
- molecular_function:
    id: GO:0019901
    label: protein kinase binding
  description: >-
    NPM1 associates with unduplicated centrosomes and acts as a licensing factor for
    centrosome duplication by physically preventing premature centriole replication. NPM1
    is a substrate of CDK2/cyclin E, which phosphorylates it at Thr199 triggering its
    dissociation from centrosomes and thereby licensing duplication. PLK2 further
    phosphorylates NPM1 at Ser4 in a Polo-box-dependent manner to trigger centriole
    duplication. The Ran-Crm1 pathway controls NPM1 centrosome association. Loss of NPM1
    centrosome function leads to unrestricted centrosome duplication and genomic instability,
    a hallmark of cancer. This represents a fundamentally distinct core activity from NPM1
    nucleolar functions.
  directly_involved_in:
    - id: GO:0010826
      label: negative regulation of centrosome duplication
    - id: GO:0010824
      label: regulation of centrosome duplication
    - id: GO:0046599
      label: regulation of centriole replication
    - id: GO:0007098
      label: centrosome cycle
  locations:
    - id: GO:0005813
      label: centrosome
    - id: GO:0031616
      label: spindle pole centrosome
  supported_by:
    - reference_id: PMID:11051553
      supporting_text: >-
        We identified nucleophosmin (NPM/B23) as a substrate of CDK2/cyclin E in
        centrosome duplication. NPM/B23 associates specifically with unduplicated
        centrosomes, and NPM/B23 dissociates from centrosomes by CDK2/cyclin E-mediated
        phosphorylation.
    - reference_id: PMID:20352051
      supporting_text: >-
        We find that Plk2 and NPM/B23 interact in vitro in a Polo-box dependent manner.
        Expression of a non-phosphorylatable NPM/B23 S4A mutant interferes with centriole
        reduplication in S-phase arrested cells and leads to a dilution of centriole
        numbers in unperturbed U2OS cells.
    - reference_id: PMID:16041368
      supporting_text: >-
        Ran-Crm1 controls NPM1 association with centrosomes for centrosome duplication
        regulation.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10211837
  title: Nucleolar protein B23 has molecular chaperone activities.
  findings: []
- id: PMID:11051553
  title: Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication.
  findings: []
- id: PMID:11420665
  title: Diverged nuclear localization of Werner helicase in human and mouse cells.
  findings: []
- id: PMID:11602260
  title: Function of nucleophosmin/B23, a nucleolar acidic protein, as a histone chaperone.
  findings: []
- id: PMID:12058066
  title: The RNA binding activity of a ribosome biogenesis factor, nucleophosmin/B23,
    is modulated by phosphorylation with a cell cycle-dependent kinase and by association
    with its subtype.
  findings: []
- id: PMID:12080348
  title: Nucleophosmin regulates the stability and transcriptional activity of p53.
  findings: []
- id: PMID:12882984
  title: Nucleophosmin interacts with and inhibits the catalytic function of eukaryotic
    initiation factor 2 kinase PKR.
  findings: []
- id: PMID:15087454
  title: Identification of nucleophosmin as an NF-kappaB co-activator for the induction
    of the human SOD2 gene.
  findings: []
- id: PMID:15144954
  title: Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein
    p53 from HDM2-mediated degradation.
  findings: []
- id: PMID:15161933
  title: Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding
    proteins.
  findings: []
- id: PMID:15184379
  title: Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin
    ligase.
  findings: []
- id: PMID:15989956
  title: ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor.
  findings: []
- id: PMID:16041368
  title: Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in
    centrosome duplication.
  findings: []
- id: PMID:16107701
  title: Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin
    transcription.
  findings: []
- id: PMID:16130169
  title: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced
    apoptosis.
  findings: []
- id: PMID:16376884
  title: 'Characterisation of the interface between nucleophosmin (NPM) and p53: potential
    role in p53 stabilisation.'
  findings: []
- id: PMID:16540653
  title: Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated
    NPM mutant.
  findings: []
- id: PMID:16648475
  title: Nucleophosmin is essential for ribosomal protein L5 nuclear export.
  findings: []
- id: PMID:16957780
  title: Antiviral action of the tumor suppressor ARF.
  findings: []
- id: PMID:17015463
  title: Interaction between ROCK II and nucleophosmin/B23 in the regulation of centrosome
    duplication.
  findings: []
- id: PMID:17318229
  title: Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor
    during cell differentiation.
  findings: []
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass spectrometry.
  findings: []
- id: PMID:17438371
  title: Detection and identification of transcription factors as interaction partners
    of alien in vivo.
  findings: []
- id: PMID:17475909
  title: The human Shwachman-Diamond syndrome protein, SBDS, associates with ribosomal
    RNA.
  findings: []
- id: PMID:17602943
  title: Physical and functional interaction between a nucleolar protein nucleophosmin/B23
    and adenovirus basic core proteins.
  findings: []
- id: PMID:18243139
  title: The nucleocapsid protein of SARS-associated coronavirus inhibits B23 phosphorylation.
  findings: []
- id: PMID:18259216
  title: The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of
    nucleophosmin and is required for rRNA processing.
  findings: []
- id: PMID:18420587
  title: Ribosomal protein S9 is a novel B23/NPM-binding protein required for normal
    cell proliferation.
  findings: []
- id: PMID:18809582
  title: Nucleophosmin serves as a rate-limiting nuclear export chaperone for the
    Mammalian ribosome.
  findings: []
- id: PMID:19160485
  title: A ribosomal protein L23-nucleophosmin circuit coordinates Mizl function with
    cell growth.
  findings: []
- id: PMID:19188445
  title: APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in the rRNA
    quality control process.
  findings: []
- id: PMID:19208757
  title: Nucleolar structure and function are regulated by the deubiquitylating enzyme
    USP36.
  findings: []
- id: PMID:19410545
  title: HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A
    at centromeres.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20075868
  title: Nucleolar retention of a translational C/EBPalpha isoform stimulates rDNA
    transcription and cell size.
  findings: []
- id: PMID:20159986
  title: Methylation of ribosomal protein S10 by protein-arginine methyltransferase
    5 regulates ribosome biogenesis.
  findings: []
- id: PMID:20352051
  title: Polo-like kinase 2-dependent phosphorylation of NPM/B23 on serine 4 triggers
    centriole duplication.
  findings: []
- id: PMID:20618440
  title: Proteomic and biochemical analysis of 14-3-3-binding proteins during C2-ceramide-induced
    apoptosis.
  findings: []
- id: PMID:20701745
  title: Karyopherin alpha7 (KPNA7), a divergent member of the importin alpha family
    of nuclear import receptors.
  findings: []
- id: PMID:21326211
  title: The SUMO system controls nucleolar partitioning of a novel mammalian ribosome
    biogenesis complex.
  findings: []
- id: PMID:21423176
  title: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role
    for β-Pix in negative regulation of focal adhesion maturation.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:21822216
  title: Nucleophosmin deposition during mRNA 3' end processing influences poly(A)
    tail length.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:22510990
  title: AKT-dependent phosphorylation of Niban regulates nucleophosmin- and MDM2-mediated
    p53 stability and cell apoptosis.
  findings: []
- id: PMID:22528486
  title: Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5
    (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation
    in hepatocellular carcinoma cells.
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding
    transcripts.
  findings: []
- id: PMID:22712502
  title: Erythroid differentiation-associated gene interacts with NPM1 (nucleophosmin/B23)
    and increases its protein stability, resisting cell apoptosis.
  findings: []
- id: PMID:22720776
  title: PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex.
  findings: []
- id: PMID:23019224
  title: DDX31 regulates the p53-HDM2 pathway and rRNA gene transcription through
    its interaction with NPM1 in renal cell carcinomas.
  findings: []
- id: PMID:23816991
  title: Exploration of binary virus-host interactions using an infectious protein
    complementation assay.
  findings: []
- id: PMID:23892143
  title: Human respiratory syncytial virus N, P and M protein interactions in HEK-293T
    cells.
  findings: []
- id: PMID:23972994
  title: ABH2 couples regulation of ribosomal DNA transcription with DNA alkylation
    repair.
  findings: []
- id: PMID:24106084
  title: Intrinsically disordered regions of nucleophosmin/B23 regulate its RNA binding
    activity through their inter- and intra-molecular association.
  findings: []
- id: PMID:24462683
  title: Interaction between nucleophosmin and HBV core protein increases HBV capsid
    assembly.
  findings: []
- id: PMID:24857377
  title: Phosphorylation of multifunctional nucleolar protein nucleophosmin (NPM1)
    by aurora kinase B is critical for mitotic progression.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25956029
  title: The Nucleolar Protein GLTSCR2 Is an Upstream Negative Regulator of the Oncogenic
    Nucleophosmin-MYC Axis.
  findings: []
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
- id: PMID:28255170
  title: Nucleophosmin Interacts with PIN2/TERF1-interacting Telomerase Inhibitor
    1 (PinX1) and Attenuates the PinX1 Inhibition on Telomerase Activity.
  findings: []
- id: PMID:28611246
  title: Inhibition of Avian Influenza A Virus Replication in Human Cells by Host
    Restriction Factor TUFM Is Correlated with Autophagy.
  findings: []
- id: PMID:29568061
  title: An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein
    interactions and subcellular localizations.
  findings: []
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
    in Intact Cell Nuclei.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  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:35709258
  title: Spatial centrosome proteome of human neural cells uncovers disease-relevant
    heterogeneity.
  findings: []
- id: PMID:38029384
  title: Proteomics analysis identifies the ribosome associated coiled-coil domain-containing
    protein-124 as a novel interaction partner of nucleophosmin-1.
  findings: []
- id: PMID:38231884
  title: ARID3C Acts as a Regulator of Monocyte-to-Macrophage Differentiation Interacting
    with NPM1.
  findings: []
- id: PMID:39251607
  title: Systematic identification of post-transcriptional regulatory modules.
  findings: []
- id: PMID:9094689
  title: Protein B23 is an important human factor for the nucleolar localization of
    the human immunodeficiency virus protein Tat.
  findings: []
- id: PMID:9121481
  title: Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated
    NPM-anaplastic lymphoma kinase fusion protein in oncogenesis.
  findings: []
- id: Reactome:R-HSA-180725
  title: Rev associates with B23
  findings: []
- id: Reactome:R-HSA-180728
  title: Association of Ran-GTP with importin-beta
  findings: []
- id: Reactome:R-HSA-180736
  title: Disassembly of the Rev-importin beta-B23:Ran-GTP complex
  findings: []
- id: Reactome:R-HSA-4086059
  title: SUMOylation of NPM1 with SUMO2,3
  findings: []
- id: Reactome:R-HSA-4086088
  title: SUMOylation of NPM1 with SUMO1
  findings: []
- id: Reactome:R-HSA-606287
  title: RSF complex binds the centromere
  findings: []
- id: Reactome:R-HSA-606289
  title: New CENPA-containing nucleosomes are deposited at the centromere
  findings: []
- id: Reactome:R-HSA-606326
  title: HJURP:CENPA complex localizes to the centromere
  findings: []
- id: Reactome:R-HSA-6801675
  title: PLK2 phosphorylates NPM1
  findings: []
- id: Reactome:R-HSA-8869542
  title: TFPA2A homodimer and NPM1 bind the HSPD1 gene promoter
  findings: []
- id: Reactome:R-HSA-8869543
  title: TFPA2A homodimer and NPM1 bind the NOP2 gene promoter
  findings: []
- id: Reactome:R-HSA-8869549
  title: TFPA2A homodimer and NPM1 bind the MYBL2 gene promoter
  findings: []
- id: Reactome:R-HSA-8869568
  title: NPM1 binds TFAP2A homodimer
  findings: []
- id: Reactome:R-HSA-9700131
  title: ALK mutants bind type I TKIs
  findings: []
- id: Reactome:R-HSA-9700179
  title: Ligand-independent dimerization of ALK fusions
  findings: []
- id: Reactome:R-HSA-9700181
  title: Autophosphorylation of ALK fusions
  findings: []
- id: Reactome:R-HSA-9700190
  title: ALK mutants bind SHC
  findings: []
- id: Reactome:R-HSA-9700193
  title: ALK mutants phosphorylate SHC1
  findings: []
- id: Reactome:R-HSA-9710914
  title: ALK fusions bind GRB2
  findings: []
- id: Reactome:R-HSA-9710917
  title: ALK fusion proteins bind PLCG1
  findings: []
- id: Reactome:R-HSA-9712078
  title: ALK mutants bind PI3KR1
  findings: []
- id: Reactome:R-HSA-9712079
  title: ALK mutants bind STAT3
  findings: []
- id: Reactome:R-HSA-9712081
  title: ALK fusions bind FRS
  findings: []
- id: Reactome:R-HSA-9712082
  title: ALK fusions phosphorylate IRS1
  findings: []
- id: Reactome:R-HSA-9712083
  title: ALK mutants bind PI3KCA
  findings: []
- id: Reactome:R-HSA-9712084
  title: PI3K synthesizes PIP3 downstream of ALK mutants
  findings: []
- id: Reactome:R-HSA-9712085
  title: ALK mutants phosphorylate STAT3
  findings: []
- id: Reactome:R-HSA-9712086
  title: ALK fusions phosphorylate PLCG1
  findings: []
- id: Reactome:R-HSA-9712087
  title: ALK fusions phosphorylate FRS
  findings: []
- id: Reactome:R-HSA-9712088
  title: ALK fusion proteins bind IRS
  findings: []
- id: Reactome:R-HSA-9724099
  title: ALK mutants:p-3Y SHC binds GRB2
  findings: []
- id: Reactome:R-HSA-9725009
  title: NPM1-ALK translocates to the nucleus
  findings: []
- id: Reactome:R-HSA-9725023
  title: NPM1-ALK fusion dimer binds SKP1:CUL1:RBX1:ZC3HC1
  findings: []
- id: Reactome:R-HSA-9725030
  title: MAPK1 phsophorylates ZC3HCF1 in a NPM-ALK-dependent manner
  findings: []
- id: Reactome:R-HSA-9727886
  title: SARS-CoV-1 SUMO-p-N binds to NPM1
  findings: []
- id: Reactome:R-HSA-9835328
  title: NPM binds PKR
  findings: []
- id: Reactome:R-HSA-9850958
  title: pY-STAT3 dimer translocates to the nucleus downstream of ALK mutants
  findings: []
- id: Reactome:R-HSA-9851090
  title: NPM1-ALK binds NPM1 and FOXM1
  findings: []
- id: DOI:10.3390/cells13151266
  title: 'Nucleophosmin: A Nucleolar Phosphoprotein Orchestrating Cellular Stress
    Responses'
  findings:
  - statement: NPM1 is a modular protein with an N-terminal oligomerization domain,
      a central acidic/disordered region contributing to histone binding, and a C-terminal
      globular nucleic-acid-binding domain including nucleolar localization determinants
      (NoLS) and key aromatic residues (W288/W290).
  - statement: NPM1 is a major driver of nucleolar LLPS, forming homotypic droplets
      and heterotypic droplets with arginine-rich proteins and rRNA that help establish
      nucleolar GC structure and ribosome-production capacity.
  - statement: Oxidation and S-glutathionylation at Cys275 triggers NPM1 release
      from the nucleolus to the nucleoplasm during nucleolar stress responses.
  - statement: NPM1 participates in DNA damage responses and repair pathway execution,
      including scaffolding/interaction with DNA repair factors and regulation by
      phosphorylation states, and interacts with p53/HDM2 regulatory circuits in the
      context of stress and genome stability.
- id: DOI:10.1101/2023.01.23.525122
  title: The stability of NPM1 oligomers regulated by acidic disordered regions controls
    the quality of liquid droplets
  findings:
  - statement: Destabilizing NPM1 oligomers (e.g. by altering acidic disordered regions
      or phosphomimetic changes at Ser125) increased droplet fluidity, supporting a
      model where post-translationally tuned oligomer stability helps regulate nucleolar
      dynamics across the cell cycle.
- id: DOI:10.3390/ijms24043161
  title: Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1)
    Mutation
  findings:
  - statement: Common exon 12 frameshift mutations disrupt the C-terminal fold/NoLS
      (including loss of key aromatic residues W288/W290) and introduce/strengthen
      nuclear export, shifting NPM1 to the cytoplasm (NPM1c+), a hallmark visualizable
      by immunohistochemistry.
- id: DOI:10.1158/2643-3230.bcd-23-0144
  title: Criteria for Diagnosis and Molecular Monitoring of NPM1-Mutated AML
  findings:
  - statement: NPM1-mutated AML is the largest molecular subgroup of adult AML,
      accounting for approximately 30-35% of adult cases and enriched in normal-karyotype
      AML (approximately 50-60%).
  - statement: NPM1 mutations are AML-specific and absent from preleukemic clonal
      hematopoiesis, making them particularly suitable MRD targets.

NPM1

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

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Question

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Target Gene/Protein Identity (from UniProt):

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

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