id: Q969K4 gene_symbol: ABTB1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ABTB1 is a cytoplasmic ankyrin-repeat and BTB/POZ-domain protein with multiple splice isoforms. It was originally described as BPOZ/elongation factor 1A-binding protein and as a PTEN-responsive growth-suppressive factor in cancer cell assays. Its domain architecture and interaction with CUL3 support membership in a cullin-associated ubiquitin ligase complex, most plausibly a CRL3 context, but specific physiological substrates and direct ubiquitin-ligase substrate-adaptor activity remain poorly characterized. alternative_products: - name: 2 {ECO:0000269|PubMed:10891360, ECO:0000269|PubMed:11494141} id: Q969K4-1 - name: 1 {ECO:0000269|PubMed:11494141} (BPOZ-1) id: Q969K4-2 sequence_note: VSP_052148 - name: 3 {ECO:0000269|PubMed:11494141} (BPOZ-3) id: Q969K4-3 sequence_note: VSP_052149 - name: 4 {ECO:0000269|PubMed:14702039} id: Q969K4-4 sequence_note: VSP_052150, VSP_052151, VSP_052152, VSP_052153 existing_annotations: - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: >- ABTB1 has BTB/POZ and ankyrin-repeat architecture and is linked to CUL3 in interaction data. The existing IBA ubiquitin-ligase-complex call is directionally sound, but the more informative complex context is a Cul3-RING ubiquitin ligase complex rather than the broad parent term. action: MODIFY reason: >- The PANTHER IBA and local UniProt/GOA evidence support ubiquitin ligase complex membership, and UniProt lists an ABTB1-CUL3 interaction. Because ABTB1 is a BTB/POZ-domain protein and the PN projection places it in the Cul3 substrate receptor branch, the appropriate replacement is the specific CRL3 complex term. This should not be extended to catalytic E3 ligase activity or substrate-adaptor activity without ABTB1-specific substrate evidence. proposed_replacement_terms: - id: GO:0031463 label: Cul3-RING ubiquitin ligase complex additional_reference_ids: - PMID:21145461 - file:human/ABTB1/ABTB1-uniprot.txt - file:human/ABTB1/ABTB1-notes.md supported_by: - reference_id: file:human/ABTB1/ABTB1-uniprot.txt supporting_text: "Q969K4; Q13618: CUL3; NbExp=5" - reference_id: PMID:21145461 supporting_text: "a large fraction of cullins are assembled with adaptor modules" - reference_id: file:human/ABTB1/ABTB1-notes.md supporting_text: >- For ABTB1, local evidence supports BTB/POZ/ankyrin architecture, CUL3 interaction, and inferred ubiquitin ligase complex membership - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: >- Cytoplasmic localization is consistent with UniProt subcellular-location curation and the HPA/GOA localization context. action: ACCEPT reason: >- ABTB1 is curated by UniProt as cytoplasmic, and the same cellular compartment is represented by independent GOA localization rows. This is a supported location for the protein, although no compartment-specific substrate has been established. additional_reference_ids: - file:human/ABTB1/ABTB1-uniprot.txt supported_by: - reference_id: file:human/ABTB1/ABTB1-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm" - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- This UniProt subcellular-location mapping is consistent with direct UniProt curation of ABTB1 as cytoplasmic. action: ACCEPT reason: >- The IEA row is a conservative mapping from UniProt subcellular-location vocabulary and agrees with the IBA cytoplasm and HPA cytosol context. additional_reference_ids: - file:human/ABTB1/ABTB1-uniprot.txt supported_by: - reference_id: file:human/ABTB1/ABTB1-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21145461 qualifier: enables review: summary: >- PMID:21145461 is the CRL-network proteomics study underlying the ABTB1-CUL3 interaction in GOA/UniProt. The generic protein-binding term should be replaced by the more specific CUL3/cullin-binding term. action: MODIFY reason: >- ABTB1-CUL3 association is informative for the proposed CRL3 complex context, but generic protein binding is not an informative molecular-function annotation. The appropriate replacement captures cullin-family protein binding, without asserting substrate-adaptor activity or a known substrate. proposed_replacement_terms: - id: GO:0097602 label: cullin family protein binding additional_reference_ids: - file:human/ABTB1/ABTB1-uniprot.txt - file:human/ABTB1/ABTB1-notes.md supported_by: - reference_id: file:human/ABTB1/ABTB1-uniprot.txt supporting_text: "Q969K4; Q13618: CUL3; NbExp=5" - reference_id: PMID:21145461 supporting_text: "the abundance of adaptor modules, rather than cycles of neddylation and CAND1 binding, drives CRL network organization" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: >- This is a proteome-scale human interactome study. ABTB1 interaction evidence from this source is useful as interaction context, but the GO term protein binding is too generic to describe ABTB1's function. action: MARK_AS_OVER_ANNOTATED reason: >- The annotation reports high-throughput interaction evidence, including partners such as CUL3 and EEF1A2 in GOA. For ABTB1, the informative curation target is the specific CUL3/cullin-binding and CRL3-complex context; generic protein binding should not be retained as a core molecular function. supported_by: - reference_id: PMID:25416956 supporting_text: "A proteome-scale map of the human interactome network" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: >- PMID:28514442 reports BioPlex AP-MS interaction mapping. ABTB1 interactions from this source are high-throughput network context rather than a specific biochemical activity. action: MARK_AS_OVER_ANNOTATED reason: >- GOA records this as generic protein binding for several ABTB1 partners. The term does not capture ABTB1's likely CRL3-complex role or any specific validated substrate relationship, so it is over-annotated. supported_by: - reference_id: PMID:28514442 supporting_text: "BioPlex 2.0 enables systems-level study of protein interactions" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31515488 qualifier: enables review: summary: >- PMID:31515488 contributes high-throughput human protein-interaction evidence, including variant-sensitive interaction context. It does not make generic protein binding an informative ABTB1 function. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction evidence may be real, but this broad term should be replaced by specific partner/context terms where warranted. It should not be used to infer ABTB1 substrate-adaptor activity without substrate-level evidence. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: >- PMID:32296183 is a reference human binary-interactome map. The ABTB1 row is useful as interaction context but not as a specific molecular-function claim. action: MARK_AS_OVER_ANNOTATED reason: >- Generic protein binding from a large-scale interactome map is not informative for ABTB1. No specific GO molecular function should be inferred from this row beyond partner-level curation when the partner and mechanism justify it. supported_by: - reference_id: PMID:32296183 supporting_text: "A reference map of the human binary protein interactome" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: >- This neurodegenerative-disease interactome study contributes ABTB1 interaction context, including ATXN1/TARDBP partners in GOA, but does not establish a core ABTB1 molecular function. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction context is peripheral to the supported ABTB1 CRL3/cytoplasmic complex picture. Generic protein binding is over-annotated and should not be retained as a core function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: >- PMID:33961781 reports dual proteome-scale interaction networks. This supports high-throughput interaction context but not a specific ABTB1 molecular function. action: MARK_AS_OVER_ANNOTATED reason: >- ABTB1 partners from this dataset are best treated as network context. The generic protein-binding annotation is too broad and should not be a core annotation. supported_by: - reference_id: PMID:33961781 supporting_text: "defining interactome structure and dynamics is required to understand cellular diversity" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: >- PMID:40205054 is a multimodal cell-map resource integrating protein interactions and imaging. Its ABTB1 interaction evidence is contextual and does not justify retaining generic protein binding. action: MARK_AS_OVER_ANNOTATED reason: >- The study is valuable for cell-map context, but protein binding remains an uninformative term for ABTB1. No ABTB1-specific substrate-adaptor activity is established by this row. supported_by: - reference_id: PMID:40205054 supporting_text: "yielding protein biophysical interactions and protein IF images for a matched set of more than 5,100 proteins" - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: >- HPA-derived cytosol localization is consistent with the broader UniProt cytoplasm annotation. action: ACCEPT reason: >- Cytosol is a reasonable supported cellular component for ABTB1 and is compatible with the proposed cytoplasmic CRL3-associated context. additional_reference_ids: - file:human/ABTB1/ABTB1-uniprot.txt supported_by: - reference_id: file:human/ABTB1/ABTB1-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm" - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:11494141 qualifier: located_in review: summary: >- The original BPOZ/PTEN paper is cited by UniProt for ABTB1 cytoplasmic localization. The cached publication is abstract-only, so the UniProt record is used as local support for this localization statement. action: ACCEPT reason: >- Cytoplasmic localization is repeatedly represented in ABTB1 curated sources. This localization is valid, while the paper's growth-suppression phenotype should not be over-translated into a detailed GO process without source-level full text. additional_reference_ids: - file:human/ABTB1/ABTB1-uniprot.txt supported_by: - reference_id: file:human/ABTB1/ABTB1-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm" references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: >- Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: PMID:10891360 title: Molecular cloning and characterization of a novel human gene containing ankyrin repeat and double BTB/POZ domain. findings: - statement: >- ABTB1/BPOZ encodes a 478 amino acid protein with ankyrin-repeat and BTB/POZ domains and was proposed to function through protein-protein interactions or complex formation. supporting_text: >- A novel human gene containing an ankyrin repeat and BTB/POZ domains (BPOZ) was isolated from a human leukocyte cDNA library - statement: >- ABTB1/BPOZ is broadly expressed in fetal tissues and may have developmentally regulated roles. supporting_text: >- ubiquitously expressed in all fetal tissues examined - id: PMID:11494141 title: Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. findings: - statement: >- BPOZ/ABTB1 was identified as a PTEN-responsive gene whose overexpression suppresses cancer-cell growth and G1/S progression in the assays described in the abstract. supporting_text: >- BPOZ were able to suppress growth of cancer cells - statement: >- The cached publication text is abstract-only and does not expose the subcellular localization details that UniProt cites from this PMID. supporting_text: >- Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. - id: PMID:21145461 title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. findings: - statement: >- The CRL-network study provides the broader framework for cullins assembled with adaptor modules, consistent with treating ABTB1-CUL3 binding as cullin-binding and CRL3-complex context rather than catalytic E3 ligase activity. supporting_text: >- a large fraction of cullins are assembled with adaptor modules - id: PMID:22689670 title: MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA. full_text_unavailable: true findings: - statement: >- ABTB1 is identified as a direct target of miR-125b in myeloid cell models, with 3'UTR luciferase reporter validation, mRNA and protein down-regulation on miR-125b overexpression, and the report describing ABTB1 as an anti-proliferative factor. This is post-transcriptional regulation context and does not by itself establish a new GO molecular function or localization for ABTB1. - id: PMID:36809527 title: Adaptive and non-adaptive gene expression responses in prostate cancer during androgen deprivation. full_text_unavailable: true findings: - statement: >- In prostate cancer, ABTB1 is an androgen-receptor-associated gene whose expression is retained under androgen-deprivation adaptation, and ABTB1 expression is a statistically significant marker of progression-free survival in TCGA prostate adenocarcinoma multivariable modeling. This is a correlative clinical association, not direct mechanistic or pathway evidence, and does not justify a new GO process annotation. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. 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:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: file:human/ABTB1/ABTB1-uniprot.txt title: UniProtKB Q969K4 ABTB1 record findings: - statement: >- UniProt curates ABTB1 as cytoplasmic and lists CUL3 among its interaction partners. supporting_text: "Q969K4; Q13618: CUL3; NbExp=5" - statement: >- UniProt also lists EEF1A2 as a reproducible ABTB1 interaction partner, but this review treats elongation-factor binding as unresolved non-core context. supporting_text: "Q969K4; Q05639: EEF1A2; NbExp=12" - statement: >- The UniProt flat file contains UniProt-only GO rows that were not present in the QuickGO GOA download used to seed this review. supporting_text: "GO; GO:0003746; F:translation elongation factor activity" - id: file:human/ABTB1/ABTB1-notes.md title: ABTB1 review notes findings: - statement: >- PN projection was evaluated conservatively; ABTB1 has CUL3/complex evidence but no ABTB1-specific substrate evidence supporting GO:1990756 in this review. supporting_text: >- I did not find ABTB1-specific substrate identification or a direct assay showing that ABTB1 bridges CUL3 to a substrate - id: file:human/ABTB1/ABTB1-deep-research-falcon.md title: Falcon deep research synthesis of ABTB1 function core_functions: - description: >- ABTB1 is best treated as a probable CUL3-associated BTB/ankyrin component of a cytoplasmic ubiquitin ligase complex. The supported molecular boundary is CUL3/cullin binding and CRL3-complex membership; no physiological ABTB1 substrate is currently established in the local evidence reviewed here. EEF1A/EEF1D binding is reproducible in interaction resources, especially the EEF1A2 IntAct/UniProt entry, but its physiological significance is unresolved and is treated as non-core interaction context rather than translation elongation factor activity. molecular_function: id: GO:0097602 label: cullin family protein binding locations: - id: GO:0005737 label: cytoplasm - id: GO:0005829 label: cytosol in_complex: id: GO:0031463 label: Cul3-RING ubiquitin ligase complex supported_by: - reference_id: file:human/ABTB1/ABTB1-uniprot.txt supporting_text: "Q969K4; Q13618: CUL3; NbExp=5" - reference_id: PMID:21145461 supporting_text: "a large fraction of cullins are assembled with adaptor modules" - reference_id: file:human/ABTB1/ABTB1-notes.md supporting_text: >- local evidence supports BTB/POZ/ankyrin architecture, CUL3 interaction, and inferred ubiquitin ligase complex membership - reference_id: file:human/ABTB1/ABTB1-uniprot.txt supporting_text: "Q969K4; Q05639: EEF1A2; NbExp=12" knowledge_gaps: - gap_statement: >- ABTB1-specific CRL3 substrate-adaptor activity remains inferential because no physiological ABTB1 substrate or direct substrate-bridging assay has been established in the reviewed evidence. boundary: >- The review accepts cullin family protein binding and Cul3-RING ubiquitin ligase complex membership. It does not yet assert ubiquitin-like ligase-substrate adaptor activity as a confirmed ABTB1 molecular function. gap_kind: - BIOLOGY - CURATION dark_aspect: MF_DARK status: OPEN significance: >- Resolving this gap would determine whether ABTB1 should receive a specific substrate-adaptor molecular-function annotation and which biological processes, if any, should be assigned based on the substrates it recruits. resolution: >- Endogenous ABTB1-CUL3 complex isolation, substrate-trapping mutants, quantitative ubiquitin-remnant proteomics, and in vitro ternary-complex and ubiquitination assays should identify direct substrates. provenance: - reference_id: file:human/ABTB1/ABTB1-notes.md supporting_text: I did not find ABTB1-specific substrate identification or a direct assay showing that ABTB1 bridges CUL3 to a substrate - reference_id: file:human/ABTB1/ABTB1-deep-research-falcon.md supporting_text: While ABTB1 is plausibly a CUL3 adaptor by domain logic and foundational BTB/POZ literature, **ABTB1-specific** reconstitution of a CUL3 complex and identification of ubiquitination substrates were not present in the retrieved full-text evidence. - gap_statement: >- The compartment where ABTB1 performs its putative CRL3/scaffold function is not well resolved. boundary: >- UniProt and the review support cytoplasmic/cytosolic context, and interaction resources support CUL3 and EEF1A/EEF1D binding. The gap is whether ABTB1 has a regulated, substrate-specific localization or subcellular pool that explains those interactions. gap_kind: - BIOLOGY - CURATION dark_aspect: CC_DARK status: OPEN significance: >- Better localization evidence would refine cellular-component annotations and distinguish a generic cytoplasmic scaffold from a specific CRL3, translation factor, or signaling compartment. resolution: >- Endogenous tagging or validated antibodies should map ABTB1 localization under basal, PTEN/miRNA, cell-cycle, and proteasome/neddylation-perturbation conditions with CUL3 and candidate substrate colocalization. provenance: - reference_id: file:human/ABTB1/ABTB1-deep-research-falcon.md supporting_text: No definitive cellular compartment localization for human ABTB1 was established from the currently retrieved excerpts; localization should be treated as **unknown/insufficiently supported** here. - reference_id: file:human/ABTB1/ABTB1-uniprot.txt supporting_text: "SUBCELLULAR LOCATION: Cytoplasm" - gap_statement: >- ABTB1's anti-proliferative/PTEN-linked role and prostate-cancer expression association remain mechanistically and contextually unresolved. boundary: >- The review accepts that ABTB1 has been linked to PTEN growth-suppressive signaling and is directly regulated by miR-125b in myeloid models, but it does not annotate ABTB1 to a specific cell-cycle, cancer, or signaling biological process from correlative or context-dependent evidence. gap_kind: - BIOLOGY - CURATION dark_aspect: BP_DARK status: OPEN significance: >- Resolving this gap would determine whether any proliferation, PTEN-pathway, miRNA-regulated, or cancer-relevant GO process is a direct ABTB1 function, or whether these findings remain disease-model context downstream of an unknown substrate/scaffold mechanism. resolution: >- Isoform-resolved ABTB1 perturbation and rescue across myeloid and prostate models, combined with substrate identification and PTEN/AR/miRNA pathway epistasis, should define which phenotypes are direct. provenance: - reference_id: PMID:11494141 supporting_text: BPOZ were able to suppress growth of cancer cells - reference_id: file:human/ABTB1/ABTB1-deep-research-falcon.md supporting_text: In prostate cancer, the authors emphasize that ABTB1 produces multiple protein forms and that it is not known which form(s) mediate growth inhibition, which is important when reconciling apparently conflicting associations across cancers. - reference_id: file:human/ABTB1/ABTB1-deep-research-falcon.md supporting_text: Association is correlative and context-specific; contrasts with anti-proliferative narrative in other systems, implying context dependence or isoform complexity. proposed_new_terms: [] suggested_questions: - question: >- Does ABTB1 have experimentally validated substrates in a CRL3 complex, or is the PN Cul3 substrate receptor assignment currently based only on domain architecture and CUL3 interaction? experts: - GO ubiquitin-proteasome curators - Proteostasis Network UPS curators - question: >- Should ABTB1 be annotated to GO:1990756 only after a substrate-bridging assay is available, or is CUL3 binding plus BTB-BACK/ankyrin architecture sufficient for a conservative IBA-style molecular-function inference? experts: - GO molecular function editors - PAINT curators - question: >- Are the EEF1A/EEF1D interactions a biologically meaningful ABTB1 function or a non-core interaction context from interactome datasets, and should the UniProt-only translation elongation factor activity IEA be treated as an erroneous keyword mapping? experts: - UniProt curators - translation-factor specialists - question: >- Given that ABTB1 is a direct miR-125b target and an anti-proliferative factor in myeloid models, yet higher ABTB1 expression correlates with worse progression-free survival in prostate cancer, are these context- or isoform-dependent roles, and should any of them map to a defensible GO biological-process term rather than remaining as correlative disease context? experts: - GO biological-process editors - cancer biology curators suggested_experiments: - experiment_type: regulatory axis validation hypothesis: >- miR-125b post-transcriptionally represses ABTB1 to relieve its anti-proliferative activity, and this axis operates in non-myeloid contexts such as prostate epithelium. description: >- Test miR-125b-dependent regulation of endogenous ABTB1 across cell types using miR-125b mimic/inhibitor with ABTB1 mRNA/protein readouts and 3'UTR reporter controls, then assess whether ABTB1 restoration reverses miR-125b-driven proliferation. - experiment_type: CRL3 substrate identification hypothesis: ABTB1 is a substrate-recognition subunit of a CUL3-RBX1 ubiquitin ligase complex. description: >- Perform ABTB1 affinity purification under native expression or low-level tagged rescue, quantify CUL3/RBX1 association, and combine ABTB1 knockout or degron-stabilization proteomics with neddylation inhibition to identify candidate ABTB1-dependent substrates. - experiment_type: substrate-bridging assay hypothesis: ABTB1 directly bridges CUL3 to one or more substrate proteins. description: >- Reconstitute ABTB1, CUL3-RBX1, and candidate substrates in vitro and test ternary complex formation plus substrate ubiquitination, using ABTB1 BTB/POZ-domain mutants as CUL3-binding controls. - experiment_type: interaction specificity review hypothesis: EEF1A/EEF1D interactions represent a reproducible but non-core ABTB1 interaction context. description: >- Validate ABTB1 interactions with EEF1A2 and EEF1D by reciprocal co-IP at endogenous expression levels and test whether ABTB1 perturbation changes elongation-factor localization, stability, or translation output.