id: Q9P2A4
gene_symbol: ABI3
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ABI3 (also known as NESH) is a member of the ABI (Abl interactor) family of adaptor proteins.
  It contains an N-terminal WAVE-binding domain, proline-rich regions, and a C-terminal SH3 domain.
  ABI3 functions as a component of the WAVE regulatory complex (WRC), occupying the Abi subunit
  position alongside WAVE2, CYFIP1, NAP1, and BRK1. Unlike its paralogs ABI1 and ABI2, ABI3 does
  not bind c-Abl and does not promote c-Abl-mediated phosphorylation of WAVE2 (PMID:17101133).
  ABI3-containing WAVE2 complexes are functionally distinct from ABI1-based complexes, showing
  reduced WAVE2 translocation to the plasma membrane and impaired lamellipodium formation
  (PMID:26428302). ABI3 is regulated by phosphorylation at S213, S216, and S342, with
  non-phosphorylated ABI3 preferentially incorporated into the WRC. ABI3 is enriched in microglia
  in the brain and is a replicated Alzheimer disease risk gene (S209F variant, OR~1.43). In mouse
  models, Abi3 loss impairs microglial ramification and tissue surveillance. ABI3 also shows
  tumor-suppressive properties when ectopically expressed, suppressing cell motility and metastatic
  dissemination (PMID:11956071) and inducing cellular senescence (PMID:21223585).
existing_annotations:
  - term:
      id: GO:0048858
      label: cell projection morphogenesis
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation based on phylogenetic inference from ABI family orthologs across species.
        ABI3 is a WRC component and the WRC is essential for actin-dependent cell projection
        formation. ABI3-containing WAVE2 complexes influence protrusion formation, though
        ABI3 specifically impairs lamellipodial protrusions while potentially favoring ventral
        protrusions (PMID:26428302). The term 'cell projection morphogenesis' is appropriately
        general for this family-level annotation.
      action: ACCEPT
      reason: >-
        As a WRC component, ABI3 modulates actin-dependent cell projections. The IBA annotation
        at this level of specificity is appropriate given the phylogenetic conservation of this
        function across ABI family members.
      supported_by:
        - reference_id: PMID:26428302
          supporting_text: >-
            the formation of peripheral lamellipodial structures was disturbed, suggesting
            that the NESH/Abi-3-based WAVE2 complex was unable to help produce lamellipodial
            protrusions
  - term:
      id: GO:0001764
      label: neuron migration
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation inferred from orthologs. ABI family members participate in
        neuron migration via actin regulation through the WRC. ABI3 is expressed in the brain,
        particularly in microglia (not neurons primarily), but WRC function in neuron migration
        is well-established for ABI1/ABI2 orthologs.
      action: KEEP_AS_NON_CORE
      reason: >-
        Neuron migration is a conserved function of ABI family members through the WRC.
        However, ABI3 is primarily enriched in microglia rather than neurons in the brain.
        The IBA inference from orthologs is phylogenetically reasonable but this is not
        a core function of ABI3 specifically.
  - term:
      id: GO:0030027
      label: lamellipodium
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for lamellipodium localization based on phylogenetic inference.
        ABI3 localizes to lamellipodia as shown by IDA evidence in PMID:17101133. This
        is consistent with its role as a WRC component, since the WRC drives
        Arp2/3-dependent actin polymerization at the leading edge.
      action: ACCEPT
      reason: >-
        Supported by direct experimental evidence (IDA from PMID:17101133) and consistent
        with ABI3 function as a WRC component. Lamellipodium localization is a core
        aspect of ABI3 biology.
      supported_by:
        - reference_id: PMID:17101133
          supporting_text: >-
            Immunoprecipitation revealed that NESH (Abi-3) is present in the Abi/WAVE complex
  - term:
      id: GO:0031209
      label: SCAR complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for SCAR/WAVE complex membership. This is very well supported
        by multiple IDA studies (PMID:17101133, PMID:26428302) and IP-MS data
        (Moraes et al. 2017). ABI3 is a bona fide component of the WAVE regulatory
        complex, occupying the Abi subunit position.
      action: ACCEPT
      reason: >-
        Core function of ABI3. Membership in the SCAR/WAVE complex is the defining
        biochemical role of ABI3. Strongly supported by multiple independent experimental
        studies.
      supported_by:
        - reference_id: PMID:17101133
          supporting_text: >-
            Immunoprecipitation revealed that NESH (Abi-3) is present in the Abi/WAVE complex.
            Our results suggest that NESH (Abi-3), like Abi-1 and Abi-2, is a component of
            the Abi/WAVE complex
        - reference_id: PMID:26428302
          supporting_text: >-
            NESH/Abi-3 was ectopically expressed in NIH3T3 cells, in which Abi-1, but not
            NESH/Abi-3, is expressed. The expression of NESH/Abi-3 caused degradation of
            endogenous Abi-1, which led to the formation of a NESH/Abi-3-based WAVE2 complex
  - term:
      id: GO:0035591
      label: signaling adaptor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for signaling adaptor activity. ABI3 functions as an adaptor protein
        within the WRC, linking upstream signals to actin cytoskeleton regulation. It contains
        an SH3 domain and proline-rich regions typical of adaptor proteins. The SH3 domain
        interacts with PAK and IRSp53 (PMID:11956071, PMID:18480067).
      action: ACCEPT
      reason: >-
        ABI3 is a well-characterized adaptor protein. Its SH3 domain mediates protein-protein
        interactions and it serves as a bridge within the WRC to couple signaling to actin
        regulation. This accurately captures the molecular function of ABI3.
      supported_by:
        - reference_id: PMID:11956071
          supporting_text: >-
            The SH3 domain of NESH seems to interact with p21-activated kinase (PAK),
            which is involved in regulation of cell motility
  - term:
      id: GO:0098858
      label: actin-based cell projection
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for actin-based cell projection localization. ABI3 localizes to
        actin-based structures as a WRC component. Experimental evidence shows it at
        lamellipodia and potentially invadopodia (PMID:26428302).
      action: ACCEPT
      reason: >-
        Consistent with ABI3 function as a WRC component that regulates actin-based
        protrusions. Well-supported by the IDA evidence for lamellipodium localization
        and the broader role in actin-based structures.
  - term:
      id: GO:0030334
      label: regulation of cell migration
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for regulation of cell migration. Strongly supported by
        experimental evidence showing that forced expression of NESH/ABI3 suppresses
        cell motility and metastatic dissemination (PMID:11956071). ABI3 modulates
        migration through its effects on WRC-dependent actin dynamics.
      action: ACCEPT
      reason: >-
        Core function of ABI3. Regulation of cell migration is one of the best-characterized
        biological roles of ABI3, supported by multiple independent studies.
      supported_by:
        - reference_id: PMID:11956071
          supporting_text: >-
            every clone of NESH transfectants caused a marked reduction in motility,
            although the clones exhibited no significant differences in intrinsic cell
            growth compared with the control cells in vitro
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        IEA annotation from UniProt subcellular location mapping. Cytoplasmic
        localization is supported by IDA evidence (GO_REF:0000054) and NAS from
        PMID:11956071. UniProt states ABI3 localizes to the cytoplasm and
        colocalizes with PAK2 at the leading edge of cells.
      action: ACCEPT
      reason: >-
        Consistent with experimental evidence for cytoplasmic localization. Broad
        IEA mapping is acceptable given strong experimental support.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16189514
    review:
      summary: >-
        Protein binding annotation from high-throughput interactome study. While ABI3
        does bind multiple proteins, 'protein binding' is uninformative. The more
        specific 'signaling adaptor activity' (GO:0035591) already captures the
        molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        'Protein binding' is too vague to be informative. ABI3 does bind proteins but
        the specific adaptor function is better captured by GO:0035591 (signaling adaptor
        activity). High-throughput interactome data does not provide mechanistic insight.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17101133
    review:
      summary: >-
        Protein binding from PMID:17101133 which demonstrated ABI3 interacts with
        WAVE2 complex components. This is more informative than generic protein binding
        as it reflects the specific WRC interaction, but the term itself is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        While the underlying interaction data from PMID:17101133 is high quality and shows
        specific binding to WAVE complex components, 'protein binding' is not an informative
        GO term. The SCAR complex membership and signaling adaptor activity annotations
        better capture this function.
      supported_by:
        - reference_id: PMID:17101133
          supporting_text: >-
            Immunoprecipitation revealed that NESH (Abi-3) is present in the Abi/WAVE complex
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19060904
    review:
      summary: >-
        Protein binding from high-throughput binary interactome mapping study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic 'protein binding' from high-throughput study is uninformative.
        More specific molecular function terms already exist for ABI3.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21516116
    review:
      summary: >-
        Protein binding from next-generation sequencing interactome dataset.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic 'protein binding' from high-throughput study is uninformative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: >-
        Protein binding from proteome-scale interactome mapping.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic 'protein binding' from high-throughput study is uninformative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27107014
    review:
      summary: >-
        Protein binding from inter-species protein-protein interaction network study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic 'protein binding' from high-throughput study is uninformative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29892012
    review:
      summary: >-
        Protein binding from interactome perturbation framework study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic 'protein binding' from high-throughput study is uninformative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >-
        Protein binding from reference binary protein interactome map.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic 'protein binding' from high-throughput study is uninformative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: >-
        Protein binding from multimodal cell maps study.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Generic 'protein binding' from high-throughput study is uninformative.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: >-
        Self-interaction of ABI3 detected in high-throughput interactome study.
        UniProt interaction data confirms ABI3 self-interaction (NbExp=4).
      action: ACCEPT
      reason: >-
        ABI3 homodimerization is supported by multiple independent high-throughput
        studies and is recorded in IntAct. This is more informative than generic
        'protein binding' and may reflect a functional oligomerization relevant to
        WRC assembly or regulation.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >-
        Additional evidence for ABI3 self-interaction from reference interactome map.
      action: ACCEPT
      reason: >-
        Independent confirmation of ABI3 homodimerization. Duplicates with different
        references are acceptable.
  - term:
      id: GO:0002357
      label: defense response to tumor cell
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation from combined automated methods, likely transferred from mouse
        ortholog data. The IMP annotation from PMID:21223585 provides direct experimental
        support showing ABI3 ectopic expression reduces tumor growth.
      action: ACCEPT
      reason: >-
        Consistent with the IMP-supported annotation from PMID:21223585 and with
        broader literature on ABI3 as a tumor suppressor. The IEA is broader but not
        incorrect.
  - term:
      id: GO:0010593
      label: negative regulation of lamellipodium assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from mouse ortholog. Supported by experimental evidence
        in PMID:26428302 showing that ABI3/NESH expression in NIH3T3 cells reduced WAVE2
        translocation to the plasma membrane and disturbed lamellipodial formation.
      action: ACCEPT
      reason: >-
        This is a well-supported function of ABI3. The ABI3-based WAVE2 complex is
        functionally distinct and impairs lamellipodial protrusion formation compared
        to ABI1-based complexes.
      supported_by:
        - reference_id: PMID:26428302
          supporting_text: >-
            the translocation of WAVE2 to the plasma membrane was significantly reduced
            and the formation of peripheral lamellipodial structures was disturbed
  - term:
      id: GO:0030027
      label: lamellipodium
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for lamellipodium localization. Consistent with IDA evidence
        from PMID:17101133 and IBA annotation.
      action: ACCEPT
      reason: >-
        Redundant with IBA and IDA annotations but not incorrect. Lamellipodium
        localization is well established for ABI3.
  - term:
      id: GO:0031209
      label: SCAR complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for SCAR complex membership. Consistent with IDA annotations
        from PMID:17101133 and PMID:26428302.
      action: ACCEPT
      reason: >-
        Core function. Redundant with IDA annotations but acceptable.
  - term:
      id: GO:0098794
      label: postsynapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from rat ortholog via Ensembl Compara. ISS annotations
        from ARUK-UCL also support postsynaptic localization (dendritic spine, postsynaptic
        density). The WRC functions in dendritic spine morphogenesis, supporting synaptic
        localization. However, ABI3 is primarily enriched in microglia rather than neurons.
      action: KEEP_AS_NON_CORE
      reason: >-
        While WRC-mediated actin regulation at the postsynapse is conserved for ABI family
        members, ABI3 is primarily expressed in microglia in the brain, not neurons. The
        synaptic annotations may be more relevant to ABI1/ABI2 and transferred to ABI3
        by orthology. Keep as non-core pending direct evidence in neurons.
  - term:
      id: GO:0098885
      label: modification of postsynaptic actin cytoskeleton
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation from rat ortholog. WRC-dependent actin modification at postsynapses
        is a known function of ABI family members. However, ABI3 is primarily microglial
        rather than neuronal in the brain.
      action: KEEP_AS_NON_CORE
      reason: >-
        Plausible by orthology and WRC function but ABI3 is not the primary ABI family
        member in neurons. This function may be more attributable to ABI1/ABI2.
  - term:
      id: GO:0098978
      label: glutamatergic synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from rat ortholog. Glutamatergic synapse localization
        may be more relevant to ABI1/ABI2 given ABI3 enrichment in microglia.
      action: KEEP_AS_NON_CORE
      reason: >-
        Transferred from rat ortholog. ABI3 is microglia-enriched in brain tissue and
        not primarily neuronal. This annotation may reflect function of other ABI
        paralogs rather than ABI3 specifically.
  - term:
      id: GO:1903077
      label: negative regulation of protein localization to plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation from mouse ortholog. Supported by experimental evidence showing
        that ABI3 expression reduces WAVE2 translocation to the plasma membrane
        (PMID:26428302).
      action: ACCEPT
      reason: >-
        Well-supported by experimental data. ABI3-containing WAVE2 complexes show
        reduced translocation to the plasma membrane compared to ABI1-containing
        complexes, consistent with this annotation.
      supported_by:
        - reference_id: PMID:26428302
          supporting_text: >-
            the translocation of WAVE2 to the plasma membrane was significantly reduced
  - term:
      id: GO:0030036
      label: actin cytoskeleton organization
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation transferred by curator judgment. ABI3 participates in actin
        cytoskeleton organization as a WRC component. The WRC activates Arp2/3-mediated
        actin nucleation and polymerization.
      action: ACCEPT
      reason: >-
        Core function of ABI3. As a WRC subunit, ABI3 directly participates in actin
        cytoskeleton organization. Well-supported by multiple studies showing effects
        on lamellipodia, cell protrusions, and actin-based structures.
  - term:
      id: GO:0002357
      label: defense response to tumor cell
    evidence_type: IMP
    original_reference_id: PMID:21223585
    review:
      summary: >-
        IMP annotation from PMID:21223585 showing that ABI3 ectopic expression reduces
        tumor growth in vitro and in vivo in thyroid and colon carcinoma cell lines.
        ABI3 expression is frequently lost in carcinomas, and re-expression reduces
        transforming activity, anchorage-independent growth, and in vivo tumor formation.
      action: KEEP_AS_NON_CORE
      reason: >-
        The experimental evidence is solid showing tumor-suppressive effects of ABI3
        re-expression. However, 'defense response to tumor cell' is not the most precise
        term for what was shown. The study demonstrates tumor suppressor activity through
        re-expression in cancer cells where ABI3 was silenced. This is more accurately
        described as negative regulation of cell proliferation or tumor suppression.
        Nevertheless, this is a secondary consequence of ABI3's primary role in actin
        regulation and cell migration, not a core evolved function.
      supported_by:
        - reference_id: PMID:21223585
          supporting_text: >-
            Ectopic expression of ABI3 was sufficient to lead to a lower transforming
            activity, reduced tumor in vitro growth properties, suppressed in vitro
            anchorage-independent growth and in vivo tumor formation while, cellular
            senescence increased
  - term:
      id: GO:2000774
      label: positive regulation of cellular senescence
    evidence_type: IMP
    original_reference_id: PMID:21223585
    review:
      summary: >-
        IMP annotation from PMID:21223585. ABI3 ectopic expression induced senescence
        in thyroid and colon carcinoma cells, accompanied by p21WAF1 upregulation and
        reduced ERK phosphorylation.
      action: KEEP_AS_NON_CORE
      reason: >-
        The experimental evidence for senescence induction is clear from PMID:21223585.
        However, this is likely a secondary consequence of ABI3 re-expression in cancer
        cells rather than a core evolved function. This effect is observed in the context
        of ectopic expression in cells where ABI3 was silenced, and the senescence
        phenotype may reflect disruption of oncogenic signaling rather than a primary
        ABI3 function.
      supported_by:
        - reference_id: PMID:21223585
          supporting_text: >-
            cellular senescence increased. These responses were accompanied by the
            up-regulation of the cell cycle inhibitor p21 WAF1 and reduced ERK
            phosphorylation and E2F1 expression
  - term:
      id: GO:0031209
      label: SCAR complex
    evidence_type: IDA
    original_reference_id: PMID:17101133
    review:
      summary: >-
        IDA annotation from PMID:17101133 demonstrating ABI3 is present in the Abi/WAVE
        complex by immunoprecipitation. This is a key finding establishing ABI3 as a
        bona fide WRC component.
      action: ACCEPT
      reason: >-
        Core function. Direct experimental evidence from immunoprecipitation showing
        ABI3 is a component of the WAVE complex.
      supported_by:
        - reference_id: PMID:17101133
          supporting_text: >-
            Immunoprecipitation revealed that NESH (Abi-3) is present in the Abi/WAVE
            complex. Our results suggest that NESH (Abi-3), like Abi-1 and Abi-2, is
            a component of the Abi/WAVE complex
  - term:
      id: GO:0043197
      label: dendritic spine
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation transferred from a rat ortholog (F1M0R2) by ARUK-UCL curators.
        WRC components are known to localize to dendritic spines where they regulate
        spine morphogenesis. However, ABI3 is primarily microglial in the brain.
      action: KEEP_AS_NON_CORE
      reason: >-
        While WRC function at dendritic spines is conserved for ABI family members,
        ABI3 is microglia-enriched in the brain. This annotation may primarily reflect
        the function of ABI1/ABI2 in neurons, transferred by sequence similarity.
  - term:
      id: GO:0043198
      label: dendritic shaft
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation transferred from rat ortholog. Similar considerations as for
        dendritic spine localization.
      action: KEEP_AS_NON_CORE
      reason: >-
        ABI3 is microglia-enriched rather than neuronal. This annotation may reflect
        function of other ABI paralogs. Keeping as non-core.
  - term:
      id: GO:0014069
      label: postsynaptic density
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation transferred from rat ortholog. Postsynaptic density localization
        is well-established for WRC components, but ABI3 is primarily microglial.
      action: KEEP_AS_NON_CORE
      reason: >-
        Same reasoning as for dendritic spine. WRC function at the PSD is conserved
        for ABI family but ABI3 enrichment in microglia suggests this is not its
        primary localization context.
  - term:
      id: GO:0051015
      label: actin filament binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation transferred from rat ortholog. ABI3 contains domains that could
        mediate interactions with actin-based structures, but direct actin filament
        binding by ABI3 itself has not been demonstrated. ABI3 functions as an adaptor
        within the WRC rather than directly binding actin filaments.
      action: UNDECIDED
      reason: >-
        There is no direct evidence for ABI3 binding actin filaments. ABI3 interacts
        with actin-regulatory complexes (WRC) but its function is as an adaptor, not
        an actin-binding protein per se. The ISS transfer may be from a different ABI
        paralog with distinct biochemical properties. More evidence needed to confirm
        direct actin filament binding by ABI3.
  - term:
      id: GO:0061001
      label: regulation of dendritic spine morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation from rat ortholog. WRC regulates dendritic spine morphogenesis
        but ABI3 is microglia-enriched, not primarily neuronal.
      action: KEEP_AS_NON_CORE
      reason: >-
        WRC function in spine morphogenesis is well-established but likely mediated
        by ABI1/ABI2 in neurons. ABI3 is primarily expressed in microglia.
  - term:
      id: GO:0099151
      label: regulation of postsynaptic density assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation from rat ortholog. Similar considerations as other synaptic
        annotations.
      action: KEEP_AS_NON_CORE
      reason: >-
        ABI3 is microglia-enriched and not the primary ABI paralog at neuronal
        synapses. Keep as non-core.
  - term:
      id: GO:1900028
      label: negative regulation of ruffle assembly
    evidence_type: NAS
    original_reference_id: PMID:18480067
    review:
      summary: >-
        NAS annotation from PMID:18480067 which identified IRSp53 as a binding partner
        of NESH/ABI3. The paper is a brief letter identifying the interaction. Previous
        work showed ABI3 over-expression blocked PDGF-stimulated membrane ruffling.
      action: ACCEPT
      reason: >-
        Negative regulation of ruffle assembly is consistent with ABI3's role in
        modulating actin-based structures. ABI3 overexpression blocks PDGF-stimulated
        membrane ruffling, and ABI3-containing WAVE2 complexes impair protrusion
        formation (PMID:26428302). This is a direct consequence of ABI3's core function
        in modulating WRC activity.
      supported_by:
        - reference_id: PMID:26428302
          supporting_text: >-
            the translocation of WAVE2 to the plasma membrane was significantly reduced
            and the formation of peripheral lamellipodial structures was disturbed
  - term:
      id: GO:0010593
      label: negative regulation of lamellipodium assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation from mouse ortholog. Strongly supported by experimental
        evidence in PMID:26428302 showing ABI3-containing WAVE2 complexes impair
        lamellipodium formation.
      action: ACCEPT
      reason: >-
        This is a core function distinguishing ABI3 from ABI1/ABI2. ABI3-based
        WAVE2 complexes are functionally distinct and impair lamellipodial protrusions.
      supported_by:
        - reference_id: PMID:26428302
          supporting_text: >-
            the NESH/Abi-3-based WAVE2 complex was unable to help produce
            lamellipodial protrusions
  - term:
      id: GO:0031209
      label: SCAR complex
    evidence_type: IDA
    original_reference_id: PMID:26428302
    review:
      summary: >-
        IDA annotation from PMID:26428302 providing detailed characterization of the
        ABI3-based WAVE2 complex. Demonstrated that ABI3 expression leads to degradation
        of endogenous ABI1 and formation of an ABI3-based WAVE2 complex.
      action: ACCEPT
      reason: >-
        Core function. Independent confirmation of SCAR/WAVE complex membership
        with detailed functional characterization of the distinct ABI3-containing complex.
      supported_by:
        - reference_id: PMID:26428302
          supporting_text: >-
            The expression of NESH/Abi-3 caused degradation of endogenous Abi-1,
            which led to the formation of a NESH/Abi-3-based WAVE2 complex
  - term:
      id: GO:1903077
      label: negative regulation of protein localization to plasma membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation from mouse ortholog. ABI3 expression reduces WAVE2 translocation
        to the plasma membrane, as shown in PMID:26428302.
      action: ACCEPT
      reason: >-
        Well-supported by experimental data. ABI3-containing WAVE2 complexes show
        reduced membrane translocation compared to ABI1-containing complexes.
      supported_by:
        - reference_id: PMID:26428302
          supporting_text: >-
            the translocation of WAVE2 to the plasma membrane was significantly reduced
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: HDA
    original_reference_id: PMID:19946888
    review:
      summary: >-
        HDA annotation from a study defining the membrane proteome of NK cells.
        ABI3 was detected in the membrane fraction by proteomics.
      action: ACCEPT
      reason: >-
        ABI3 as a WRC component can associate with membranes, particularly at the
        leading edge where it colocalizes with PAK2. Detection in membrane proteome
        of NK cells is consistent with this.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000054
    review:
      summary: >-
        IDA annotation from LIFEdb based on intracellular localization of expressed
        fusion proteins in living cells. Consistent with UniProt subcellular location
        annotation.
      action: ACCEPT
      reason: >-
        Cytoplasmic localization is well-established for ABI3. Supported by multiple
        independent evidence sources.
  - term:
      id: GO:0018108
      label: peptidyl-tyrosine phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:17101133
    negated: true
    review:
      summary: >-
        CORRECT negative annotation. PMID:17101133 explicitly tested and showed that
        "NESH (Abi-3) had no such effect" on promoting c-Abl-mediated phosphorylation,
        unlike Abi-1 and Abi-2 which do promote this activity. This negative annotation
        correctly captures that ABI3/NESH does NOT participate in peptidyl-tyrosine
        phosphorylation processes.
      action: ACCEPT
      reason: >-
        Important negative annotation that distinguishes ABI3 from its paralogs ABI1
        and ABI2. PMID:17101133 directly tested and demonstrated this difference.
      supported_by:
        - reference_id: PMID:17101133
          supporting_text: >-
            Although Abi-2, like Abi-1, promoted the c-Abl-mediated phosphorylation
            of Mena and WAVE2, NESH (Abi-3) had no such effect. This difference was
            likely due to their binding abilities as to c-Abl
  - term:
      id: GO:0030027
      label: lamellipodium
    evidence_type: IDA
    original_reference_id: PMID:17101133
    review:
      summary: >-
        IDA annotation from PMID:17101133. ABI3 was shown to be present in the
        Abi/WAVE complex which localizes to lamellipodia where it regulates
        Rac-dependent actin polymerization.
      action: ACCEPT
      reason: >-
        Direct experimental evidence supports lamellipodium localization of ABI3
        as part of the WAVE complex.
      supported_by:
        - reference_id: PMID:17101133
          supporting_text: >-
            Immunoprecipitation revealed that NESH (Abi-3) is present in the Abi/WAVE
            complex
  - term:
      id: GO:0030334
      label: regulation of cell migration
    evidence_type: IDA
    original_reference_id: PMID:11956071
    review:
      summary: >-
        IDA annotation from PMID:11956071 showing forced NESH/ABI3 expression
        suppresses cell motility. NESH transfectants showed marked reduction in
        motility and reduced tumor metastatic potential in vivo.
      action: ACCEPT
      reason: >-
        Core function. One of the earliest and best-characterized biological roles
        of ABI3. Direct experimental demonstration of cell migration regulation.
      supported_by:
        - reference_id: PMID:11956071
          supporting_text: >-
            every clone of NESH transfectants caused a marked reduction in motility,
            although the clones exhibited no significant differences in intrinsic
            cell growth compared with the control cells in vitro. The NESH
            transfectants also exhibited significant reduction in tumor metastatic
            potential in vivo
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: NAS
    original_reference_id: PMID:11956071
    review:
      summary: >-
        NAS annotation for cytoplasmic localization from PMID:11956071. The paper
        describes NESH as an intracellular SH3 adapter protein.
      action: ACCEPT
      reason: >-
        Consistent with other evidence for cytoplasmic localization. The paper
        describes cytoplasmic distribution and colocalization with PAK2 at the
        leading edge of cells.
      supported_by:
        - reference_id: PMID:11956071
          supporting_text: >-
            The SH3 domain of NESH seems to interact with p21-activated kinase (PAK),
            which is involved in regulation of cell motility
references:
  - id: GO_REF:0000024
    title: >-
      Manual transfer of experimentally-verified manual GO annotation data
      to orthologs by curator judgment of sequence similarity
    findings: []
  - 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:0000054
    title: >-
      Gene Ontology annotation based on curation of intracellular
      localizations of expressed fusion proteins in living cells
    findings: []
  - id: GO_REF:0000107
    title: >-
      Automatic transfer of experimentally verified manual GO annotation
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:11956071
    title: >-
      Forced expression of NESH suppresses motility and metastatic
      dissemination of malignant cells.
    findings:
      - statement: >-
          NESH/ABI3 forced expression suppresses cell motility and metastatic
          dissemination. NESH interacts with PAK via its SH3 domain and decreases
          PAK phosphorylation at Thr402.
        supporting_text: >-
          every clone of NESH transfectants caused a marked reduction in motility,
          although the clones exhibited no significant differences in intrinsic cell
          growth compared with the control cells in vitro. The NESH transfectants also
          exhibited significant reduction in tumor metastatic potential in vivo.
  - id: PMID:16189514
    title: >-
      Towards a proteome-scale map of the human protein-protein interaction
      network.
    findings: []
  - id: PMID:17101133
    title: >-
      NESH (Abi-3) is present in the Abi/WAVE complex but does not promote
      c-Abl-mediated phosphorylation.
    findings:
      - statement: >-
          ABI3/NESH is present in the Abi/WAVE complex by immunoprecipitation but
          does not bind c-Abl and does not promote c-Abl-mediated phosphorylation
          of Mena or WAVE2, distinguishing it from ABI1 and ABI2.
        supporting_text: >-
          Immunoprecipitation revealed that NESH (Abi-3) is present in the Abi/WAVE
          complex. Our results suggest that NESH (Abi-3), like Abi-1 and Abi-2, is a
          component of the Abi/WAVE complex, but likely plays a different role in the
          regulation of c-Abl.
  - id: PMID:18480067
    title: >-
      Insulin receptor substrate protein 53 (IRSp53) as a binding partner
      of antimetastasis molecule NESH, a member of Abelson interactor protein
      family.
    findings:
      - statement: >-
          IRSp53 identified as a binding partner of NESH/ABI3. IRSp53 is involved
          in PDGF-stimulated membrane ruffling.
        supporting_text: >-
          Insulin receptor substrate protein 53 (IRSp53) as a binding partner of
          antimetastasis molecule NESH, a member of Abelson interactor protein family.
  - id: PMID:19060904
    title: An empirical framework for binary interactome mapping.
    findings: []
  - id: PMID:19946888
    title: Defining the membrane proteome of NK cells.
    findings:
      - statement: >-
          ABI3 detected in the membrane proteome of NK cells by high-throughput
          proteomics.
        supporting_text: >-
          The present study was initiated to define the composition of the membrane
          proteome of the Natural Killer (NK) like cell line YTS
  - id: PMID:21223585
    title: >-
      ABI3 ectopic expression reduces in vitro and in vivo cell growth
      properties while inducing senescence.
    findings:
      - statement: >-
          ABI3 re-expression in thyroid and colon carcinoma cells reduces transforming
          activity, inhibits anchorage-independent growth, suppresses in vivo tumor
          formation, and induces cellular senescence via p21WAF1 upregulation and
          ERK phosphorylation reduction.
  - id: PMID:21516116
    title: Next-generation sequencing to generate interactome datasets.
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:26428302
    title: >-
      The NESH/Abi-3-based WAVE2 complex is functionally distinct from the
      Abi-1-based WAVE2 complex.
    findings:
      - statement: >-
          ABI3 expression in NIH3T3 cells causes degradation of endogenous ABI1 and
          formation of a distinct ABI3-based WAVE2 complex that reduces WAVE2
          translocation to the plasma membrane and impairs lamellipodial protrusions.
          In v-src transformed cells, ABI3 promotes invadopodia formation under
          certain conditions.
  - id: PMID:27107014
    title: >-
      An inter-species protein-protein interaction network across vast
      evolutionary distance.
    findings: []
  - id: PMID:29892012
    title: >-
      An interactome perturbation framework prioritizes damaging missense
      mutations for developmental disorders.
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:40205054
    title: >-
      Multimodal cell maps as a foundation for structural and functional
      genomics.
    findings: []
core_functions:
  - description: >-
      Component of the WAVE regulatory complex (WRC/SCAR complex), occupying the
      Abi subunit position. ABI3 forms a heteropentameric complex with WAVE2, CYFIP1,
      NAP1, and BRK1 that couples upstream signals (Rac, Arf GTPases) to Arp2/3-mediated
      actin nucleation and polymerization.
    molecular_function:
      id: GO:0035591
      label: signaling adaptor activity
    locations:
      - id: GO:0031209
        label: SCAR complex
    directly_involved_in:
      - id: GO:0030036
        label: actin cytoskeleton organization
    supported_by:
      - reference_id: PMID:17101133
        supporting_text: >-
          Immunoprecipitation revealed that NESH (Abi-3) is present in the Abi/WAVE
          complex. Our results suggest that NESH (Abi-3), like Abi-1 and Abi-2, is
          a component of the Abi/WAVE complex
      - reference_id: PMID:26428302
        supporting_text: >-
          The expression of NESH/Abi-3 caused degradation of endogenous Abi-1,
          which led to the formation of a NESH/Abi-3-based WAVE2 complex
  - description: >-
      Modulates actin-dependent cell migration. ABI3 expression suppresses cell motility
      and metastatic dissemination. The ABI3-containing WAVE2 complex is functionally
      distinct from the ABI1-containing complex, reducing WAVE2 translocation to the
      plasma membrane and impairing lamellipodium formation. ABI3 also interacts with
      PAK and IRSp53 via its SH3 domain to regulate migration-related signaling.
    molecular_function:
      id: GO:0035591
      label: signaling adaptor activity
    directly_involved_in:
      - id: GO:0030334
        label: regulation of cell migration
    supported_by:
      - reference_id: PMID:11956071
        supporting_text: >-
          every clone of NESH transfectants caused a marked reduction in motility,
          although the clones exhibited no significant differences in intrinsic
          cell growth compared with the control cells in vitro
      - reference_id: PMID:26428302
        supporting_text: >-
          the translocation of WAVE2 to the plasma membrane was significantly reduced
          and the formation of peripheral lamellipodial structures was disturbed
  - description: >-
      Negative regulation of lamellipodium assembly and membrane ruffling.
      ABI3-based WAVE2 complexes specifically impair the formation of peripheral
      lamellipodial structures, distinguishing ABI3 from ABI1 and ABI2 in terms
      of protrusion type regulation.
    molecular_function:
      id: GO:0035591
      label: signaling adaptor activity
    directly_involved_in:
      - id: GO:0010593
        label: negative regulation of lamellipodium assembly
    supported_by:
      - reference_id: PMID:26428302
        supporting_text: >-
          the NESH/Abi-3-based WAVE2 complex was unable to help produce
          lamellipodial protrusions
suggested_questions:
  - question: Does ABI3 directly bind actin filaments, or does it solely function as an adaptor within the WRC?
  - question: Is ABI3 expressed in neurons as well as microglia, and does it have neuron-specific functions?
  - question: How does the S209F Alzheimer disease risk variant affect ABI3 incorporation into the WRC and microglial function?
  - question: What is the precise mechanism by which ABI3 phosphorylation at S213/S216/S342 regulates its WRC incorporation?
suggested_experiments:
  - description: Direct actin filament binding assays (e.g., co-sedimentation) with purified ABI3 protein to test whether ABI3 has intrinsic actin-binding activity
  - description: Single-cell RNA-seq or spatial transcriptomics to clarify ABI3 expression across brain cell types in human tissue
  - description: In vitro WRC reconstitution with ABI3 vs ABI1 to measure differences in Arp2/3 activation kinetics
  - description: CRISPR knock-in of the S209F variant in human iPSC-derived microglia to assess effects on migration, phagocytosis, and WRC dynamics