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