id: Q8N961 gene_symbol: ABTB2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ABTB2 is a large ankyrin-repeat and BTB/POZ-domain protein with protein-protein interaction domains and isoform diversity. Direct experimental work in pancreatic ductal adenocarcinoma models supports a substrate-adaptor-like role in which ABTB2 binds TRAP1, promotes TRAP1 ubiquitination-dependent degradation, and suppresses Wnt/beta-catenin and PI3K/Akt signaling. ABTB2 has been detected in the nucleoplasm, but its normal tissue substrates and broader physiological roles remain incompletely defined. alternative_products: - name: '1' id: Q8N961-1 - name: '2' id: Q8N961-2 sequence_note: VSP_046439 existing_annotations: - term: id: GO:0046982 label: protein heterodimerization activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- This InterPro-derived annotation is consistent with ABTB2 containing protein-interaction domains, including histone-fold-like, ankyrin-repeat, and BTB/POZ features, but it is too broad to describe ABTB2's best-supported molecular function. action: MARK_AS_OVER_ANNOTATED reason: >- Retain the domain context but do not treat generic heterodimerization as a core function. The direct ABTB2 literature supports a more informative substrate-adaptor-like role in TRAP1 ubiquitination-dependent degradation, captured below as GO:1990756. additional_reference_ids: - PMID:41322190 - file:human/ABTB2/ABTB2-deep-research-manual.md supported_by: - reference_id: UniProt:Q8N961 supporting_text: 'DR InterPro; IPR009072; Histone-fold.' - reference_id: PMID:41322190 supporting_text: >- ABTB2 interacts with tumour necrosis factor receptor-associated protein 1 (TRAP1), promoting its ubiquitin-dependent degradation - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36931259 qualifier: enables review: summary: >- The IPI annotation records a 14-3-3 epsilon/YWHAE interaction detected in a broad 14-3-3 interactome study. This supports an ABTB2 protein interaction but not a specific molecular activity. action: MARK_AS_OVER_ANNOTATED reason: >- GO:0005515 is intentionally generic and is not useful as a retained core molecular-function annotation. ABTB2's direct, more informative function is better represented as ubiquitin-like ligase-substrate adaptor activity. additional_reference_ids: - PMID:41322190 - file:human/ABTB2/ABTB2-deep-research-manual.md supported_by: - reference_id: UniProt:Q8N961 supporting_text: 'CC Q8N961; P62258: YWHAE; NbExp=2; IntAct=EBI-11603395, EBI-356498;' - reference_id: PMID:36931259 supporting_text: >- Here, we map the interactomes of all human 14-3-3 paralogs - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: >- HPA immunofluorescence supports nucleoplasm localization. Direct ABTB2 functional work also links the protein to intracellular protein-complex contexts, but localization is not itself the core proteostasis function. action: KEEP_AS_NON_CORE reason: >- Keep as a supported localization/context annotation. It should not be used to infer a nuclear-specific core function, since the strongest mechanistic evidence concerns ABTB2-dependent TRAP1 ubiquitination and degradation in cancer models. additional_reference_ids: - PMID:41322190 - file:human/ABTB2/ABTB2-deep-research-manual.md - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:41322190 qualifier: enables review: summary: >- Lyu et al. identify TRAP1 as an ABTB2-interacting protein and show that ABTB2 overexpression increases TRAP1 ubiquitination and promotes TRAP1 degradation. The same study reports ABTB2 interaction with cullin-3, making the PN-projected Cul3 substrate-receptor context supportable for ABTB2. action: NEW reason: >- This is the most informative molecular-function term for the direct ABTB2 evidence. It captures ABTB2's substrate-adaptor-like role in bringing a ubiquitin-ligase system to a substrate, while avoiding a catalytic E3-ligase annotation. The older BPOZ-2/TdT and BPOZ-2/eEF1A1 literature was not used as primary ABTB2 evidence because that nomenclature overlaps with ABTB1; the 2025 ABTB2/TRAP1 study provides direct gene-specific support. additional_reference_ids: - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv - file:human/ABTB2/ABTB2-deep-research-manual.md supported_by: - reference_id: PMID:41322190 supporting_text: >- Co-immunoprecipitation using Abs specific to ABTB2 and TRAP1, followed by western blotting, confirmed the specific interaction between ABTB2 and TRAP1 - reference_id: PMID:41322190 supporting_text: >- multiple mono-ubiquitinated TRAP1 (Figures 8F and S10) in ABTB2-OE cells, suggesting that ABTB2-induced protein ubiquitination contributes to TRAP1 degradation - reference_id: PMID:41322190 supporting_text: >- We also found that ABTB2 interacts with cullin-3 (Figure S9) - reference_id: file:human/ABTB2/ABTB2-deep-research-manual.md supporting_text: >- Direct ABTB2 evidence supports a substrate-adaptor-like role for TRAP1 ubiquitination-dependent degradation. - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:41322190 qualifier: involved_in review: summary: >- ABTB2 overexpression increases pan-protein ubiquitination and TRAP1 ubiquitination, with TRAP1 degradation downstream of the ABTB2-TRAP1 interaction. action: NEW reason: >- Add as a biological-process companion to the molecular-function adaptor annotation. The evidence supports ABTB2 involvement in TRAP1 protein ubiquitination, while the molecular-function annotation should remain adaptor activity rather than catalytic ubiquitin ligase activity. additional_reference_ids: - file:human/ABTB2/ABTB2-deep-research-manual.md supported_by: - reference_id: PMID:41322190 supporting_text: >- Using western blotting, we detected abundant ubiquitination of whole proteins (Figure 8E) and multiple mono-ubiquitinated TRAP1 (Figures 8F and S10) in ABTB2-OE cells - reference_id: PMID:41322190 supporting_text: >- ABTB2 promotes TRAP1 degradation via ubiquitination (Figure 8) - reference_id: file:human/ABTB2/ABTB2-deep-research-manual.md supporting_text: >- Add `GO:0016567 protein ubiquitination` as a new biological-process companion annotation references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: - statement: >- InterPro-based annotation projected a generic protein heterodimerization activity term to ABTB2 from domain associations. supporting_text: >- The ABTB2 GOA record includes an IEA annotation to GO:0046982 protein heterodimerization activity with GO_REF:0000002 as the source reference. - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: - statement: >- Immunofluorescence-based curation supports nucleoplasm localization for ABTB2. supporting_text: >- The ABTB2 GOA record includes an IDA annotation to GO:0005654 nucleoplasm with GO_REF:0000052 as the source reference. - id: PMID:36931259 title: A central chaperone-like role for 14-3-3 proteins in human cells. findings: - statement: >- ABTB2 was identified as an interactor of 14-3-3 epsilon (YWHAE) in a systematic mapping of human 14-3-3 paralog interactomes. supporting_text: >- Here, we map the interactomes of all human 14-3-3 paralogs - id: PMID:41322190 title: Mechanistic and functional characterization of ABTB2 as a novel target for pancreatic cancer therapy. findings: - statement: >- ABTB2 interacts with TRAP1 and promotes TRAP1 ubiquitination-dependent degradation in pancreatic cancer models. supporting_text: >- Transcriptomic analysis, immunoprecipitation, and functional assays demonstrated that ABTB2 interacts with tumour necrosis factor receptor-associated protein 1 (TRAP1), promoting its ubiquitin-dependent degradation - statement: >- The authors report that ABTB2 also interacts with cullin-3, supporting a substrate-adaptor-like model. supporting_text: >- We also found that ABTB2 interacts with cullin-3 (Figure S9) - id: UniProt:Q8N961 title: UniProt record for ABTB2 (Q8N961) findings: - statement: ABTB2 contains ankyrin-repeat and BTB/POZ-domain features. supporting_text: >- FT /note="BTB" - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv title: Proteostasis PN projected annotation report findings: - statement: >- The Proteostasis PN projection places ABTB2 in the Cul3 substrate-receptor branch and projects GO:1990756. supporting_text: >- ABTB2 Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul3 substrate receptor|BTB-BACK, variant|ankyrin - id: file:human/ABTB2/ABTB2-deep-research-manual.md title: Manual deep research fallback for ABTB2 PN review findings: - statement: >- Manual fallback review supports accepting GO:1990756 for ABTB2 based on direct ABTB2-TRAP1 ubiquitination/degradation and reported ABTB2-cullin-3 interaction. supporting_text: >- Direct ABTB2 evidence supports a substrate-adaptor-like role for TRAP1 ubiquitination-dependent degradation. core_functions: - description: >- ABTB2 acts as a BTB/POZ substrate-adaptor-like protein for ubiquitin-dependent degradation of TRAP1 in pancreatic cancer models, consistent with the Proteostasis PN Cul3 substrate-receptor projection. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity directly_involved_in: - id: GO:0016567 label: protein ubiquitination substrates: - id: UniProtKB:Q12931 label: TRAP1 supported_by: - reference_id: PMID:41322190 supporting_text: >- ABTB2 promotes TRAP1 degradation via ubiquitination (Figure 8). We also found that ABTB2 interacts with cullin-3 (Figure S9) suggested_questions: - question: >- Does endogenous ABTB2 form a native CRL3 complex with CUL3 in non-cancer tissues, and is TRAP1 a physiological substrate outside pancreatic cancer models? - question: >- What additional ABTB2 substrates explain its tissue-specific and disease-context effects? suggested_experiments: - description: >- Test endogenous ABTB2-CUL3-TRAP1 complex formation with reciprocal co-IP, proximity ligation, and BTB-domain mutant rescue in cells with native ABTB2 expression. hypothesis: >- ABTB2 uses its BTB/POZ domain to recruit CUL3 while its substrate-recognition regions engage TRAP1. experiment_type: co-immunoprecipitation and mutant rescue - description: >- Measure TRAP1 ubiquitination and stability after ABTB2 loss or rescue with CUL3 depletion, proteasome inhibition, and ubiquitin-linkage/site mapping. hypothesis: >- ABTB2-dependent TRAP1 degradation requires a CUL3 ubiquitin-ligase complex. experiment_type: ubiquitination and protein-turnover assay