id: O15169
gene_symbol: AXIN1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  AXIN1 (Axis inhibition protein 1) is a cytosolic scaffold protein that serves as
  the core
  component of the beta-catenin destruction complex, which also includes APC, GSK3B,
  and CK1.
  AXIN1 coordinates the phosphorylation and subsequent ubiquitination of beta-catenin,
  thereby
  negatively regulating the canonical Wnt signaling pathway. Key functional domains
  include:
  an N-terminal tankyrase-binding motif, an RGS domain for APC binding, a GSK3B-binding
  helix
  (aa 383-400), a beta-catenin binding region, and a C-terminal DIX domain that mediates
  polymerization and formation of cytoplasmic condensates ("degradasomes"). AXIN1
  is regulated
  by tankyrase-mediated ADP-ribosylation followed by RNF146-dependent ubiquitination
  and
  degradation. Loss-of-function mutations in AXIN1 are associated with hepatocellular
  carcinoma
  due to aberrant Wnt pathway activation. AXIN1 also has secondary roles in TGF-beta
  signaling
  (promoting Smad7 degradation via Arkadia) and JNK signaling, and participates in
  the AXIN1-HIPK2-TP53
  complex upon UV irradiation.
existing_annotations:
  - term:
      id: GO:0060090
      label: molecular adaptor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 functions as a molecular adaptor/scaffold by bringing together components
        of the
        beta-catenin destruction complex (GSK3B, APC, CK1, beta-catenin). This adaptor
        function
        is directly demonstrated in PMID:9601641 and is the core function of AXIN1.
      action: ACCEPT
      reason: >-
        IBA annotation is well-supported. AXIN1 is defined as a scaffold protein that
        coordinates
        assembly of the destruction complex [PMID:9601641]. Multiple experimental
        studies confirm
        this adaptor function.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Axin acts as a scaffold upon which APC, beta-catenin and
            GSK3 beta assemble to coordinate the regulation of beta-catenin signaling."
        - reference_id: file:human/AXIN1/AXIN1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 binds to protein kinases GSK3B (through a defined alpha-helix at aa
        383-400) and
        CK1, which are essential for its function in the destruction complex.
      action: ACCEPT
      reason: >-
        AXIN1 directly binds GSK3B and CK1 kinases as part of its scaffold function.
        The GSK3B-binding
        helix is structurally characterized [PDB:1O9U]. This is a core function.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Human Axin (hAxin) binds directly to beta-catenin, GSK3
            beta, and APC in vitro, and the endogenous proteins are found in a complex
            in cells."
  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Negative regulation of canonical Wnt signaling is THE core function of AXIN1.
        By scaffolding
        the destruction complex, AXIN1 promotes beta-catenin phosphorylation and degradation,
        thereby restraining Wnt target gene transcription.
      action: ACCEPT
      reason: >-
        This is the primary biological function of AXIN1, extensively documented in
        the literature
        and supported by genetic and biochemical evidence. Loss of AXIN1 function
        leads to elevated
        beta-catenin and Wnt pathway activation.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Overexpression of hAxin strongly promoted the downregulation
            of wild-type beta-catenin in colon cancer cells"
        - reference_id: PMID:10644691
          supporting_text: "PP2C expression relieves Axin-mediated repression of LEF-1-dependent
            transcription"
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 is predominantly cytoplasmic but can translocate to the nucleus under
        specific
        conditions such as UV irradiation (where it colocalizes with DAXX in the AXIN1-HIPK2-TP53
        complex).
      action: ACCEPT
      reason: >-
        Nuclear localization is documented experimentally [PMID:12072559, PMID:21383061].
        While
        not the primary site of AXIN1 function, it represents a real localization
        pattern.
      supported_by:
        - reference_id: PMID:12072559
          supporting_text: "Subcellular distribution of Wnt pathway proteins in normal
            and neoplastic colon"
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 can localize to the plasma membrane, particularly during Wnt signaling
        when it is
        recruited to LRP5/6 receptors. Membrane localization is regulated by MACF1.
      action: ACCEPT
      reason: >-
        Plasma membrane localization is consistent with AXIN1's role in Wnt signalosome
        assembly
        and its interaction with LRP5/6 co-receptors upon Wnt stimulation. Documented
        by
        immunohistochemistry in PMID:12072559.
  - term:
      id: GO:0008013
      label: beta-catenin binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 directly binds beta-catenin through a defined binding region (aa 434-502).
        This
        interaction is essential for AXIN1's function in promoting beta-catenin phosphorylation
        and degradation.
      action: ACCEPT
      reason: >-
        Beta-catenin binding is a core molecular function of AXIN1, well-documented
        experimentally.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Human Axin (hAxin) binds directly to beta-catenin, GSK3
            beta, and APC in vitro"
  - term:
      id: GO:0030877
      label: beta-catenin destruction complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 is a core component of the beta-catenin destruction complex. It serves
        as the
        central scaffold that brings together APC, GSK3B, CK1, and beta-catenin.
      action: ACCEPT
      reason: >-
        Membership in the beta-catenin destruction complex is THE defining characteristic
        of
        AXIN1 function. This is extensively documented in the literature.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Axin acts as a scaffold upon which APC, beta-catenin and
            GSK3 beta assemble"
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 binds to E3 ubiquitin ligases including RNF111 (Arkadia) and RNF146.
        The RNF111
        interaction promotes Smad7 degradation. RNF146 binding leads to AXIN1 ubiquitination
        following ADP-ribosylation by tankyrase.
      action: ACCEPT
      reason: >-
        Ubiquitin ligase binding is functionally important for both AXIN1's role in
        promoting
        Smad7 degradation and for AXIN1's own regulation via the tankyrase-RNF146
        axis.
      supported_by:
        - reference_id: PMID:16601693
          supporting_text: "Axin activates TGF-beta signaling by forming a multimeric
            complex consisting of Smad7 and ubiquitin E3 ligase Arkadia"
  - term:
      id: GO:0032436
      label: positive regulation of proteasomal ubiquitin-dependent protein 
        catabolic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 promotes the proteasomal degradation of beta-catenin by facilitating
        its
        phosphorylation, which leads to recognition by beta-TrCP E3 ligase and ubiquitination.
      action: ACCEPT
      reason: >-
        This accurately describes AXIN1's downstream effect on beta-catenin, which
        is targeted
        for proteasomal degradation after being phosphorylated by the destruction
        complex.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Overexpression of hAxin strongly promoted the downregulation
            of wild-type beta-catenin"
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 self-associates (homodimerizes) through its DIX domain. This polymerization
        is
        important for formation of cytoplasmic condensates/degradasomes.
      action: ACCEPT
      reason: >-
        AXIN1 homodimerization/polymerization via the DIX domain is well-documented
        and
        functionally important for destruction complex assembly and condensate formation.
      supported_by:
        - reference_id: PMID:10811618
          supporting_text: "Structural basis of the Axin-adenomatous polyposis coli
            interaction"
  - term:
      id: GO:0048468
      label: cell development
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1's role in Wnt signaling regulation impacts cell development processes.
        Wnt
        signaling is a major developmental pathway.
      action: KEEP_AS_NON_CORE
      reason: >-
        While AXIN1 clearly affects developmental processes through Wnt pathway regulation,
        "cell development" is a broad pleiotropic outcome rather than a direct molecular
        function.
        The core function is Wnt pathway regulation; developmental effects are downstream.
  - term:
      id: GO:0070411
      label: I-SMAD binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        AXIN1 binds to inhibitory SMADs including SMAD7. This interaction promotes
        Smad7
        degradation via Arkadia (RNF111) and enhances TGF-beta signaling.
      action: ACCEPT
      reason: >-
        I-SMAD (Smad7) binding is experimentally validated [PMID:16601693, PMID:18593713]
        and
        represents a legitimate secondary function of AXIN1 as a scaffold in TGF-beta
        signaling.
      supported_by:
        - reference_id: PMID:16601693
          supporting_text: "Axin activates TGF-beta signaling by forming a multimeric
            complex consisting of Smad7 and ubiquitin E3 ligase Arkadia"
        - reference_id: PMID:18593713
          supporting_text: "A Smad7-Axin interaction disassociates GSK-3beta and beta-catenin
            from Axin"
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        IEA annotation from UniProt subcellular location mapping. Nuclear localization
        has
        experimental support.
      action: ACCEPT
      reason: >-
        Consistent with IBA annotation above and IDA evidence from PMID:12072559 and
        PMID:21383061.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Cytoplasmic localization is the predominant localization for AXIN1 and the
        site of
        destruction complex function.
      action: ACCEPT
      reason: >-
        AXIN1 is primarily cytoplasmic where it forms the destruction complex. Well-supported
        by multiple experimental studies.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Plasma membrane localization is consistent with AXIN1's recruitment to Wnt
        receptors.
      action: ACCEPT
      reason: >-
        Consistent with IBA annotation above and experimental evidence.
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        This IEA annotation is derived from UniProt keyword KW-0053 (Apoptosis). UniProt
        notes
        AXIN1 as a "Component of the AXIN1-HIPK2-TP53 complex which controls cell
        growth,
        apoptosis and development" and that AXIN1 "Facilitates the phosphorylation
        of TP53 by
        HIPK2 upon ultraviolet irradiation." However, this represents a secondary/pleiotropic
        function rather than AXIN1's core function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        AXIN1's core function is as a scaffold in the Wnt/beta-catenin pathway. While
        AXIN1
        participates in the AXIN1-HIPK2-TP53 complex that can influence apoptosis
        upon UV
        irradiation, this is a secondary function. The deep research document makes
        no mention
        of apoptosis as a primary function. Any apoptotic effects are likely downstream/pleiotropic
        consequences of Wnt pathway modulation or secondary functions in stress response,
        not
        the core biochemical function of the protein.
      additional_reference_ids:
        - PMID:17210684
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        Generic membrane localization. AXIN1 can associate with the plasma membrane.
      action: ACCEPT
      reason: >-
        While more specific than needed (plasma membrane is more informative), not
        incorrect.
  - term:
      id: GO:0016055
      label: Wnt signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        AXIN1 is involved in the Wnt signaling pathway as a negative regulator.
      action: MODIFY
      reason: >-
        While technically correct, this term is too broad. AXIN1 specifically negatively
        regulates
        canonical Wnt signaling. The more specific term GO:0090090 (negative regulation
        of
        canonical Wnt signaling pathway) is already present and preferred.
      proposed_replacement_terms:
        - id: GO:0090090
          label: negative regulation of canonical Wnt signaling pathway
  - term:
      id: GO:0030178
      label: negative regulation of Wnt signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        AXIN1 negatively regulates Wnt signaling. This is accurate but less specific
        than
        the canonical Wnt pathway annotation.
      action: ACCEPT
      reason: >-
        Correct annotation. AXIN1 is primarily known for regulating canonical Wnt
        signaling,
        but this broader term is acceptable as IEA.
  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation from InterPro domain mapping (Axin-like family). This correctly
        captures
        the core function.
      action: ACCEPT
      reason: >-
        Core function of AXIN1, supported by domain analysis and experimental evidence.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10481074
    review:
      summary: >-
        Interaction with GSK3B demonstrated via GSK3-binding peptide studies.
      action: MODIFY
      reason: >-
        "Protein binding" is too generic. The interaction is specifically with GSK3B,
        which
        is better captured by GO:0019901 (protein kinase binding) or more specifically
        GO:0120283 (protein serine/threonine kinase binding).
      proposed_replacement_terms:
        - id: GO:0120283
          label: protein serine/threonine kinase binding
      supported_by:
        - reference_id: PMID:10481074
          supporting_text: A GSK3-binding peptide from FRAT1 selectively 
            inhibits the GSK3-catalysed phosphorylation of axin and 
            beta-catenin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10644691
    review:
      summary: >-
        Interaction with PP2CA (PPM1A) demonstrated - protein phosphatase that dephosphorylates
        AXIN1.
      action: MODIFY
      reason: >-
        The specific interaction is with a protein phosphatase. A more informative
        term would
        be appropriate if one exists for phosphatase binding.
      proposed_replacement_terms:
        - id: GO:0019899
          label: enzyme binding
      supported_by:
        - reference_id: PMID:10644691
          supporting_text: Protein phosphatase 2Calpha dephosphorylates axin and
            activates LEF-1-dependent transcription.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10811618
    review:
      summary: >-
        Structural characterization of AXIN1-APC interaction. The paper provides crystal
        structure of the Axin-APC interaction interface.
      action: MODIFY
      reason: >-
        The specific interaction is with APC tumor suppressor. While no specific "APC
        binding"
        term exists, this interaction is functionally important for destruction complex
        assembly.
      proposed_replacement_terms:
        - id: GO:0019904
          label: protein domain specific binding
      supported_by:
        - reference_id: PMID:10811618
          supporting_text: Structural basis of the Axin-adenomatous polyposis 
            coli interaction.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11738041
    review:
      summary: >-
        Structure of phosphorylated GSK3B with FRATtide peptide that inhibits beta-catenin
        phosphorylation; context involves AXIN1-GSK3B interaction.
      action: MODIFY
      reason: >-
        Interaction with GSK3B is specifically protein kinase binding.
      proposed_replacement_terms:
        - id: GO:0120283
          label: protein serine/threonine kinase binding
      supported_by:
        - reference_id: PMID:11738041
          supporting_text: The structure of phosphorylated GSK-3beta complexed 
            with a peptide, FRATtide, that inhibits beta-catenin 
            phosphorylation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16169070
    review:
      summary: >-
        High-throughput protein-protein interaction network study.
      action: ACCEPT
      reason: >-
        Generic protein binding from large-scale study. While less informative, not
        incorrect.
        Multiple specific interactions were identified.
      supported_by:
        - reference_id: PMID:16169070
          supporting_text: 'A human protein-protein interaction network: a resource
            for annotating the proteome.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16293619
    review:
      summary: >-
        Study of beta-catenin-ligand interactions including AXIN1.
      action: MODIFY
      reason: >-
        The specific interaction is with beta-catenin, which has a specific binding
        term.
      proposed_replacement_terms:
        - id: GO:0008013
          label: beta-catenin binding
      supported_by:
        - reference_id: PMID:16293619
          supporting_text: '2005 Nov 17. Thermodynamics of beta-catenin-ligand interactions:
            the roles of the N- and C-terminal tails in modulating binding affinity.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16601693
    review:
      summary: >-
        Interaction with SMAD7 and RNF111 (Arkadia) demonstrated.
      action: MODIFY
      reason: >-
        The specific interactions are with SMAD7 (I-SMAD binding) and RNF111 (ubiquitin
        ligase
        binding), which are captured by more specific terms.
      proposed_replacement_terms:
        - id: GO:0070411
          label: I-SMAD binding
        - id: GO:0031625
          label: ubiquitin protein ligase binding
      supported_by:
        - reference_id: PMID:16601693
          supporting_text: Apr 6. Axin is a scaffold protein in TGF-beta 
            signaling that promotes degradation of Smad7 by Arkadia.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17318175
    review:
      summary: >-
        Study of PP1 regulation of the destruction complex; demonstrates AXIN1-PP1CA
        and
        AXIN1-GSK3A/B interactions.
      action: MODIFY
      reason: >-
        Specific kinase and phosphatase interactions are documented.
      proposed_replacement_terms:
        - id: GO:0120283
          label: protein serine/threonine kinase binding
      supported_by:
        - reference_id: PMID:17318175
          supporting_text: Feb 22. Protein phosphatase 1 regulates assembly and 
            function of the beta-catenin degradation complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17318191
    review:
      summary: >-
        Study of Bcr-Abl effects on beta-catenin stabilization; AXIN1 interactions
        with
        beta-catenin and GSK3B.
      action: MODIFY
      reason: >-
        Specific interactions with beta-catenin and GSK3B are better captured by specific
        terms.
      proposed_replacement_terms:
        - id: GO:0008013
          label: beta-catenin binding
      supported_by:
        - reference_id: PMID:17318191
          supporting_text: Bcr-Abl stabilizes beta-catenin in chronic myeloid 
            leukemia through its tyrosine phosphorylation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17510365
    review:
      summary: >-
        Study of WTX (AMER1) negative regulation of Wnt signaling; interactions with
        multiple
        destruction complex components.
      action: ACCEPT
      reason: >-
        Multiple interactions demonstrated; generic protein binding acceptable.
      supported_by:
        - reference_id: PMID:17510365
          supporting_text: Wilms tumor suppressor WTX negatively regulates 
            WNT/beta-catenin signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17601533
    review:
      summary: >-
        Study in C. elegans of Axin-like proteins.
      action: ACCEPT
      reason: >-
        Interaction with GSK3B ortholog demonstrated.
      supported_by:
        - reference_id: PMID:17601533
          supporting_text: 2007 Jun 6. Two functionally distinct Axin-like 
            proteins regulate canonical Wnt signaling in C.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18786926
    review:
      summary: >-
        Study of DDEF (ASAP1) interaction with APC SAMP repeats.
      action: ACCEPT
      reason: >-
        Context involves AXIN1 interactions in the APC complex.
      supported_by:
        - reference_id: PMID:18786926
          supporting_text: 2008 Sep 11. Identification of a link between the 
            SAMP repeats of adenomatous polyposis coli tumor suppressor and the 
            Src homology 3 domain of DDEF.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19131971
    review:
      summary: >-
        AXIN1 promotes c-Myc degradation by scaffolding a destruction complex for
        c-Myc.
      action: ACCEPT
      reason: >-
        Demonstrates AXIN1-MYC interaction as part of a c-Myc degradation complex.
      supported_by:
        - reference_id: PMID:19131971
          supporting_text: The Axin1 scaffold protein promotes formation of a 
            degradation complex for c-Myc.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19166851
    review:
      summary: >-
        Kaiso as a bimodal modulator for Wnt signaling; AXIN1-beta-catenin interactions.
      action: MODIFY
      reason: >-
        Specific interaction with beta-catenin.
      proposed_replacement_terms:
        - id: GO:0008013
          label: beta-catenin binding
      supported_by:
        - reference_id: PMID:19166851
          supporting_text: 2009 Jan 21. Kaiso is a bimodal modulator for 
            Wnt/beta-catenin signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19202075
    review:
      summary: >-
        Beta-arrestin links endothelin A receptor to beta-catenin signaling; AXIN1
        interactions.
      action: ACCEPT
      reason: >-
        Multiple interactions in Wnt signaling context.
      supported_by:
        - reference_id: PMID:19202075
          supporting_text: Beta-arrestin links endothelin A receptor to 
            beta-catenin signaling to induce ovarian cancer cell invasion and 
            metastasis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19249679
    review:
      summary: >-
        ATDC promotes Wnt signaling by stabilizing beta-catenin; interacts with AXIN1.
      action: ACCEPT
      reason: >-
        Novel interactor identified.
      supported_by:
        - reference_id: PMID:19249679
          supporting_text: Oncogenic function of ATDC in pancreatic cancer 
            through Wnt pathway activation and beta-catenin stabilization.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19303846
    review:
      summary: >-
        DISC1 regulates neuronal progenitor proliferation via GSK3B-beta-catenin signaling;
        AXIN1-GSK3B context.
      action: ACCEPT
      reason: >-
        Destruction complex interactions.
      supported_by:
        - reference_id: PMID:19303846
          supporting_text: Disrupted in schizophrenia 1 regulates neuronal 
            progenitor proliferation via modulation of GSK3beta/beta-catenin 
            signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19390532
    review:
      summary: >-
        AXIN1 localizes to centrosomes and is involved in microtubule nucleation;
        interacts
        with gamma-tubulin.
      action: ACCEPT
      reason: >-
        Novel function for AXIN1 in microtubule organization.
      supported_by:
        - reference_id: PMID:19390532
          supporting_text: Axin localizes to the centrosome and is involved in 
            microtubule nucleation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19759537
    review:
      summary: >-
        Tankyrase inhibition stabilizes AXIN1; demonstrates AXIN1-tankyrase interaction
        and
        its role in AXIN1 turnover.
      action: MODIFY
      reason: >-
        Specific interaction with tankyrase (PARP enzyme). Enzyme binding is more
        appropriate.
      proposed_replacement_terms:
        - id: GO:0019899
          label: enzyme binding
      supported_by:
        - reference_id: PMID:19759537
          supporting_text: Tankyrase inhibition stabilizes axin and antagonizes 
            Wnt signalling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20080667
    review:
      summary: >-
        DAB2IP modulates EMT; AXIN1 interactions in Wnt context.
      action: ACCEPT
      reason: >-
        Novel interactor.
      supported_by:
        - reference_id: PMID:20080667
          supporting_text: Role of DAB2IP in modulating 
            epithelial-to-mesenchymal transition and prostate cancer metastasis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21057547
    review:
      summary: >-
        AXIN1 is an essential co-activator for PML in p53 activation; demonstrates
        AXIN1-TP53
        interaction.
      action: MODIFY
      reason: >-
        Specific interaction with p53 (TP53).
      proposed_replacement_terms:
        - id: GO:0002039
          label: p53 binding
      supported_by:
        - reference_id: PMID:21057547
          supporting_text: Nov 8. AXIN is an essential co-activator for the 
            promyelocytic leukemia protein in p53 activation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21242974
    review:
      summary: >-
        PRMT1 methylation increases AXIN1 stability; interactions with beta-catenin
        and GSK3B.
      action: ACCEPT
      reason: >-
        Multiple interactions demonstrated.
      supported_by:
        - reference_id: PMID:21242974
          supporting_text: Methylation by protein arginine methyltransferase 1 
            increases stability of Axin, a negative regulator of Wnt signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21245303
    review:
      summary: >-
        DVL interacts with AXIN1 DIX domain to interfere with beta-catenin regulation.
      action: ACCEPT
      reason: >-
        AXIN1-DVL interaction through DIX domain polymerization interface.
      supported_by:
        - reference_id: PMID:21245303
          supporting_text: Dishevelled interacts with the DIX domain 
            polymerization interface of Axin to interfere with its function in 
            down-regulating β-catenin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21988832
    review:
      summary: >-
        Human liver protein interaction network study.
      action: ACCEPT
      reason: >-
        Large-scale interaction study.
      supported_by:
        - reference_id: PMID:21988832
          supporting_text: Toward an understanding of the protein interaction 
            network of the human liver.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22153077
    review:
      summary: >-
        Structural basis for tankyrase substrate recognition; AXIN1-TNKS2 interaction.
      action: MODIFY
      reason: >-
        Specific interaction with tankyrase TNKS2.
      proposed_replacement_terms:
        - id: GO:0019899
          label: enzyme binding
      supported_by:
        - reference_id: PMID:22153077
          supporting_text: Structural basis and sequence rules for substrate 
            recognition by Tankyrase explain the basis for cherubism disease.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22682247
    review:
      summary: >-
        Wnt signaling through inhibition of beta-catenin degradation in an intact
        AXIN1 complex.
      action: ACCEPT
      reason: >-
        Multiple destruction complex interactions.
      supported_by:
        - reference_id: PMID:22682247
          supporting_text: Wnt signaling through inhibition of β-catenin 
            degradation in an intact Axin1 complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22773187
    review:
      summary: >-
        DP1 promotes biphasic Wnt states during neural patterning; AXIN1 interactions.
      action: ACCEPT
      reason: >-
        Wnt pathway context.
      supported_by:
        - reference_id: PMID:22773187
          supporting_text: Dual functions of DP1 promote biphasic Wnt-on and 
            Wnt-off states during anteroposterior neural patterning.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23455922
    review:
      summary: >-
        Interlaboratory AP-MS reproducibility study.
      action: ACCEPT
      reason: >-
        Large-scale interaction study.
      supported_by:
        - reference_id: PMID:23455922
          supporting_text: Interlaboratory reproducibility of large-scale human 
            protein-complex analysis by standardized AP-MS.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23602568
    review:
      summary: >-
        CMGC kinase interaction landscape; GSK3A/B interactions.
      action: MODIFY
      reason: >-
        Specific kinase interactions.
      proposed_replacement_terms:
        - id: GO:0120283
          label: protein serine/threonine kinase binding
      supported_by:
        - reference_id: PMID:23602568
          supporting_text: 2013 Apr 18. The protein interaction landscape of the
            human CMGC kinase group.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24976009
    review:
      summary: >-
        YAP/TAZ incorporation in the beta-catenin destruction complex.
      action: ACCEPT
      reason: >-
        Novel interactions with YAP1 in destruction complex context.
      supported_by:
        - reference_id: PMID:24976009
          supporting_text: YAP/TAZ incorporation in the β-catenin destruction 
            complex orchestrates the Wnt response.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25241761
    review:
      summary: >-
        Proximity ligation assay profiling of endogenous protein interactions in Wnt
        pathway.
      action: ACCEPT
      reason: >-
        Wnt pathway interactions validated.
      supported_by:
        - reference_id: PMID:25241761
          supporting_text: Oct 9. Using an in situ proximity ligation assay to 
            systematically profile endogenous protein-protein interactions in a 
            pathway network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25873176
    review:
      summary: >-
        TGIF governs a feed-forward network empowering Wnt signaling; AXIN1-TGIF1
        interaction.
      action: ACCEPT
      reason: >-
        Novel interactor in Wnt pathway.
      supported_by:
        - reference_id: PMID:25873176
          supporting_text: TGIF governs a feed-forward network that empowers Wnt
            signaling to drive mammary tumorigenesis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26496610
    review:
      summary: >-
        Human interactome in three quantitative dimensions.
      action: ACCEPT
      reason: >-
        Large-scale quantitative interactome study.
      supported_by:
        - reference_id: PMID:26496610
          supporting_text: Oct 22. A human interactome in three quantitative 
            dimensions organized by stoichiometries and abundances.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26871637
    review:
      summary: >-
        Alternative splicing expansion of protein interaction capabilities.
      action: ACCEPT
      reason: >-
        Large-scale splicing-interaction study.
      supported_by:
        - reference_id: PMID:26871637
          supporting_text: Widespread Expansion of Protein Interaction 
            Capabilities by Alternative Splicing.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27098453
    review:
      summary: >-
        WDR26 is a new partner of AXIN1 in canonical Wnt signaling.
      action: ACCEPT
      reason: >-
        Novel interactor in Wnt pathway characterized.
      supported_by:
        - reference_id: PMID:27098453
          supporting_text: May 3. WDR26 is a new partner of Axin1 in the 
            canonical Wnt signaling pathway.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29568061
    review:
      summary: >-
        AP-MS and BioID compatible MAC-tag for interaction and localization mapping.
      action: ACCEPT
      reason: >-
        Large-scale interaction study.
      supported_by:
        - reference_id: PMID:29568061
          supporting_text: An AP-MS- and BioID-compatible MAC-tag enables 
            comprehensive mapping of protein interactions and subcellular 
            localizations.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32707033
    review:
      summary: >-
        Kinase interaction network expands functional and disease roles of kinases.
      action: ACCEPT
      reason: >-
        Large-scale kinase interaction study.
      supported_by:
        - reference_id: PMID:32707033
          supporting_text: 2020 Jul 23. Kinase Interaction Network Expands 
            Functional and Disease Roles of Human Kinases.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: >-
        Interactome mapping of neurodegenerative disease proteins.
      action: ACCEPT
      reason: >-
        Large-scale interaction study.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of 
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
            Aggregation in Affected Brains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        Dual proteome-scale networks reveal cell-specific interactome remodeling.
      action: ACCEPT
      reason: >-
        Large-scale interaction study.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: >-
        OpenCell endogenous tagging for cellular organization cartography.
      action: ACCEPT
      reason: >-
        Large-scale localization and interaction study.
      supported_by:
        - reference_id: PMID:35271311
          supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography
            of human cellular organization.'
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:10811618
    review:
      summary: >-
        AXIN1 homodimerization demonstrated in structural study of AXIN1-APC interaction.
      action: ACCEPT
      reason: >-
        Self-association/homodimerization is important for AXIN1 function and condensate
        formation via DIX domain.
      supported_by:
        - reference_id: PMID:10811618
          supporting_text: Structural basis of the Axin-adenomatous polyposis 
            coli interaction.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:16169070
    review:
      summary: >-
        High-throughput interaction network study includes AXIN1 self-interaction.
      action: ACCEPT
      reason: >-
        Homodimerization confirmed.
      supported_by:
        - reference_id: PMID:16169070
          supporting_text: 'A human protein-protein interaction network: a resource
            for annotating the proteome.'
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:21245303
    review:
      summary: >-
        DVL-AXIN1 interaction via DIX domain polymerization interface; includes AXIN1
        homo-oligomerization.
      action: ACCEPT
      reason: >-
        Homodimerization via DIX domain demonstrated.
      supported_by:
        - reference_id: PMID:21245303
          supporting_text: Dishevelled interacts with the DIX domain 
            polymerization interface of Axin to interfere with its function in 
            down-regulating β-catenin.
  - term:
      id: GO:0002039
      label: p53 binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 interacts with TP53 as part of the AXIN1-HIPK2-TP53 complex.
      action: KEEP_AS_NON_CORE
      reason: >-
        TP53 binding is demonstrated but represents a secondary function of AXIN1
        in stress
        response, not its core function in Wnt signaling.
      additional_reference_ids:
        - PMID:17210684
  - term:
      id: GO:0005938
      label: cell cortex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Cell cortex localization transferred from mouse ortholog.
      action: ACCEPT
      reason: >-
        Consistent with AXIN1 localization at cell periphery/plasma membrane.
  - term:
      id: GO:0008013
      label: beta-catenin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from mouse ortholog. Beta-catenin binding is a core function.
      action: ACCEPT
      reason: >-
        Core function, well-supported by experimental evidence.
  - term:
      id: GO:0015630
      label: microtubule cytoskeleton
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 has been shown to localize to centrosomes and microtubule organizing
        centers.
      action: KEEP_AS_NON_CORE
      reason: >-
        Microtubule localization is documented [PMID:19390532] but represents a secondary
        localization/function, not the primary cytoplasmic destruction complex function.
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from mouse ortholog. AXIN1 binds GSK3B and CK1 kinases.
      action: ACCEPT
      reason: >-
        Core function - kinase binding is essential for destruction complex scaffolding.
  - term:
      id: GO:0019904
      label: protein domain specific binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 binds specific domains including APC SAMP repeats and beta-catenin armadillo
        repeats.
      action: ACCEPT
      reason: >-
        AXIN1 binds specific domains of its interaction partners.
  - term:
      id: GO:0030877
      label: beta-catenin destruction complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from mouse ortholog. Core complex membership.
      action: ACCEPT
      reason: >-
        Defining characteristic of AXIN1.
  - term:
      id: GO:0031410
      label: cytoplasmic vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Cytoplasmic vesicle localization from mouse ortholog.
      action: KEEP_AS_NON_CORE
      reason: >-
        May relate to membrane trafficking or Wnt signalosome dynamics, but not a
        primary
        localization site for AXIN1 function.
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation. AXIN1 binds E3 ligases RNF146 and RNF111.
      action: ACCEPT
      reason: >-
        Important for both AXIN1 regulation (RNF146) and AXIN1 function in Smad7 degradation
        (RNF111).
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 is part of the beta-catenin destruction complex.
      action: ACCEPT
      reason: >-
        AXIN1 is part of multiple protein complexes including the destruction complex.
  - term:
      id: GO:0035591
      label: signaling adaptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 functions as a signaling adaptor in Wnt and TGF-beta pathways.
      action: ACCEPT
      reason: >-
        Core function - AXIN1 is a scaffold/adaptor protein.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from mouse ortholog. AXIN1 homodimerizes via DIX domain.
      action: ACCEPT
      reason: >-
        Self-association is important for destruction complex function and condensate
        formation.
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 homodimerizes through its DIX domain.
      action: ACCEPT
      reason: >-
        DIX domain-mediated homodimerization is well-documented.
  - term:
      id: GO:0046330
      label: positive regulation of JNK cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 activates JNK signaling independently of Wnt signaling.
      action: KEEP_AS_NON_CORE
      reason: >-
        JNK activation is a legitimate secondary function of AXIN1 distinct from its
        Wnt
        pathway role, but not the core function.
      additional_reference_ids:
        - PMID:12192039
      supported_by:
        - reference_id: PMID:12192039
          supporting_text: I-mfa domain proteins interact with Axin and affect 
            its regulation of the Wnt and c-Jun N-terminal kinase signaling 
            pathways.
  - term:
      id: GO:0070411
      label: I-SMAD binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA from mouse ortholog. AXIN1 binds SMAD7.
      action: ACCEPT
      reason: >-
        Experimentally validated [PMID:16601693].
  - term:
      id: GO:0070412
      label: R-SMAD binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 interaction with R-SMADs including SMAD3.
      action: ACCEPT
      reason: >-
        Part of AXIN1's role in TGF-beta signaling.
  - term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 acts as adaptor bringing together substrates (Smad7, beta-catenin) and
        E3 ligases.
      action: ACCEPT
      reason: >-
        AXIN1 bridges substrates to E3 ligases in both Wnt (beta-catenin to beta-TrCP)
        and
        TGF-beta (Smad7 to Arkadia) pathways.
  - term:
      id: GO:1990909
      label: Wnt signalosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        AXIN1 is recruited to the Wnt signalosome upon Wnt stimulation.
      action: ACCEPT
      reason: >-
        Part of AXIN1's role in Wnt signal transduction.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        IDA from HPA immunofluorescence data showing nucleoplasm localization.
      action: ACCEPT
      reason: >-
        AXIN1 can localize to nucleus under certain conditions.
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        IDA from HPA immunofluorescence data showing nucleolus localization.
      action: KEEP_AS_NON_CORE
      reason: >-
        Nucleolar localization may be cell type or condition dependent; not the primary
        site of AXIN1 function.
  - term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    evidence_type: NAS
    original_reference_id: PMID:9601641
    review:
      summary: >-
        AXIN1 promotes proteasomal degradation of beta-catenin as part of the destruction
        complex function.
      action: ACCEPT
      reason: >-
        Core function - AXIN1 scaffolds the machinery that leads to beta-catenin
        ubiquitination and proteasomal degradation.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Overexpression of hAxin strongly promoted the downregulation
            of wild-type beta-catenin in colon cancer cells"
  - term:
      id: GO:0043539
      label: protein serine/threonine kinase activator activity
    evidence_type: IDA
    original_reference_id: PMID:9601641
    review:
      summary: >-
        AXIN1 dramatically facilitates GSK3B phosphorylation of APC and beta-catenin
        by
        bringing kinase and substrates together.
      action: ACCEPT
      reason: >-
        Core function - AXIN1 acts as a scaffold to enhance GSK3B kinase activity
        toward
        its substrates in the destruction complex.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "hAxin dramatically facilitated the phosphorylation of
            APC and beta-catenin by GSK3 beta in vitro"
  - term:
      id: GO:0030877
      label: beta-catenin destruction complex
    evidence_type: IDA
    original_reference_id: PMID:18593713
    review:
      summary: >-
        IDA evidence for destruction complex membership from study of Smad7-Axin interaction.
      action: ACCEPT
      reason: >-
        Core complex membership.
      supported_by:
        - reference_id: PMID:18593713
          supporting_text: 2008 Jun 30. Smad7 stabilizes beta-catenin binding to
            E-cadherin complex and promotes cell-cell adhesion.
  - term:
      id: GO:0120283
      label: protein serine/threonine kinase binding
    evidence_type: IPI
    original_reference_id: PMID:18593713
    review:
      summary: >-
        AXIN1 binds GSK3B as demonstrated in this study.
      action: ACCEPT
      reason: >-
        GSK3B binding is a core function.
      supported_by:
        - reference_id: PMID:18593713
          supporting_text: 2008 Jun 30. Smad7 stabilizes beta-catenin binding to
            E-cadherin complex and promotes cell-cell adhesion.
  - term:
      id: GO:1904885
      label: beta-catenin destruction complex assembly
    evidence_type: IDA
    original_reference_id: PMID:18593713
    review:
      summary: >-
        AXIN1 is required for assembly of the destruction complex.
      action: ACCEPT
      reason: >-
        Core function - AXIN1 is the central scaffold for destruction complex assembly.
      supported_by:
        - reference_id: PMID:18593713
          supporting_text: 2008 Jun 30. Smad7 stabilizes beta-catenin binding to
            E-cadherin complex and promotes cell-cell adhesion.
  - term:
      id: GO:0031398
      label: positive regulation of protein ubiquitination
    evidence_type: IMP
    original_reference_id: PMID:16601693
    review:
      summary: >-
        AXIN1 promotes Smad7 ubiquitination by recruiting Arkadia E3 ligase.
      action: ACCEPT
      reason: >-
        Demonstrated function in TGF-beta signaling.
      supported_by:
        - reference_id: PMID:16601693
          supporting_text: "Axin and Arkadia cooperate with each other in promoting
            Smad7 ubiquitination"
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:16601693
    review:
      summary: >-
        AXIN1 binds Arkadia (RNF111) E3 ubiquitin ligase.
      action: ACCEPT
      reason: >-
        Interaction with E3 ligases is important for AXIN1 function.
      supported_by:
        - reference_id: PMID:16601693
          supporting_text: "Axin activates TGF-beta signaling by forming a multimeric
            complex consisting of Smad7 and ubiquitin E3 ligase Arkadia"
  - term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IMP
    original_reference_id: PMID:16601693
    review:
      summary: >-
        AXIN1 acts as adaptor bringing Smad7 substrate to Arkadia E3 ligase.
      action: ACCEPT
      reason: >-
        Scaffold/adaptor function between substrate and E3 ligase.
      supported_by:
        - reference_id: PMID:16601693
          supporting_text: "Axin is a scaffold protein in TGF-beta signaling that
            promotes degradation of Smad7 by Arkadia"
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-195275
    review:
      summary: >-
        TAS from Reactome pathway for phosphorylation of APC in the destruction complex.
      action: ACCEPT
      reason: >-
        Cytosolic localization is the primary site of AXIN1 function in the destruction
        complex.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-195280
    review:
      summary: >-
        TAS from Reactome - dissociation of beta-catenin from Axin and association
        with
        phospho-APC.
      action: ACCEPT
      reason: >-
        Cytosolic localization is primary.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-195283
    review:
      summary: >-
        TAS from Reactome - GSK3 phosphorylation of beta-catenin at Ser37.
      action: ACCEPT
      reason: >-
        Cytosolic destruction complex function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-195287
    review:
      summary: >-
        TAS from Reactome - GSK3 phosphorylation of beta-catenin at Thr41.
      action: ACCEPT
      reason: >-
        Cytosolic destruction complex function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-195300
    review:
      summary: >-
        TAS from Reactome - GSK3 phosphorylation of beta-catenin at Ser33.
      action: ACCEPT
      reason: >-
        Cytosolic destruction complex function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-195304
    review:
      summary: >-
        TAS from Reactome - Association of beta-catenin with destruction complex.
      action: ACCEPT
      reason: >-
        Cytosolic destruction complex function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-195318
    review:
      summary: >-
        TAS from Reactome - CK1alpha phosphorylation of beta-catenin at Ser45.
      action: ACCEPT
      reason: >-
        Cytosolic destruction complex function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2130279
    review:
      summary: >-
        TAS from Reactome - Beta-catenin association with SCF(beta-TrCP) complex.
      action: ACCEPT
      reason: >-
        Cytosolic destruction complex function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2130282
    review:
      summary: >-
        TAS from Reactome - Degradation of ubiquitinated beta-catenin.
      action: ACCEPT
      reason: >-
        Cytosolic destruction complex function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2130286
    review:
      summary: >-
        TAS from Reactome - Multi-ubiquitination of phospho-beta-catenin.
      action: ACCEPT
      reason: >-
        Cytosolic destruction complex function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5229343
    review:
      summary: >-
        TAS from Reactome - AXIN phosphorylation in destruction complex.
      action: ACCEPT
      reason: >-
        Cytosolic destruction complex function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5339713
    review:
      summary: >-
        TAS from Reactome - Misspliced GSK3beta mutants stabilize beta-catenin.
      action: ACCEPT
      reason: >-
        Cytosolic context for Wnt signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21087614
    review:
      summary: >-
        Study of natively unfolded scaffolding regions of AXIN1; interaction with
        GSK3B
        demonstrated.
      action: ACCEPT
      reason: >-
        Structural characterization of AXIN1 interactions.
      supported_by:
        - reference_id: PMID:21087614
          supporting_text: 2010 Nov 16. Critical scaffolding regions of the 
            tumor suppressor Axin1 are natively unfolded.
  - term:
      id: GO:0008013
      label: beta-catenin binding
    evidence_type: IPI
    original_reference_id: PMID:21087614
    review:
      summary: >-
        AXIN1-beta-catenin interaction demonstrated in structural study.
      action: ACCEPT
      reason: >-
        Core function.
      supported_by:
        - reference_id: PMID:21087614
          supporting_text: 2010 Nov 16. Critical scaffolding regions of the 
            tumor suppressor Axin1 are natively unfolded.
  - term:
      id: GO:0060090
      label: molecular adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:21087614
    review:
      summary: >-
        IDA evidence for adaptor activity from structural study of AXIN1 scaffolding
        regions.
      action: ACCEPT
      reason: >-
        Core function.
      supported_by:
        - reference_id: PMID:21087614
          supporting_text: 2010 Nov 16. Critical scaffolding regions of the 
            tumor suppressor Axin1 are natively unfolded.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28546513
    review:
      summary: >-
        SIAH E3 ligases promote Wnt signaling by mediating AXIN1 degradation; AXIN1-SIAH1/SIAH2
        interactions.
      action: ACCEPT
      reason: >-
        Novel E3 ligase interaction regulating AXIN1 turnover.
      supported_by:
        - reference_id: PMID:28546513
          supporting_text: May 25. The SIAH E3 ubiquitin ligases promote 
            Wnt/β-catenin signaling through mediating Wnt-induced Axin 
            degradation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4839734
    review:
      summary: >-
        TAS from Reactome - AXIN mutants destabilize destruction complex.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: IC
    original_reference_id: PMID:9601641
    review:
      summary: >-
        Inferred from Curator based on beta-catenin destruction complex membership.
      action: ACCEPT
      reason: >-
        Core function, logically inferred from scaffold role in destruction complex.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Axin acts as a scaffold upon which APC, beta-catenin and
            GSK3 beta assemble to coordinate the regulation of beta-catenin signaling"
  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:10644691
    review:
      summary: >-
        IDA evidence showing AXIN1-mediated repression of LEF-1-dependent transcription.
      action: ACCEPT
      reason: >-
        Core function directly demonstrated.
      supported_by:
        - reference_id: PMID:10644691
          supporting_text: "PP2C expression relieves Axin-mediated repression of LEF-1-dependent
            transcription"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28829046
    review:
      summary: >-
        GID8 is a beta-catenin nuclear retention factor; AXIN1 interactions with GID8,
        GSK3B,
        and beta-catenin.
      action: ACCEPT
      reason: >-
        Novel interactor GID8 characterized.
      supported_by:
        - reference_id: PMID:28829046
          supporting_text: Twa1/Gid8 is a β-catenin nuclear retention factor in 
            Wnt signaling and colorectal tumorigenesis.
  - term:
      id: GO:0035591
      label: signaling adaptor activity
    evidence_type: TAS
    original_reference_id: PMID:21799911
    review:
      summary: >-
        TAS from review of RNF146 regulation of tankyrase and AXIN1.
      action: ACCEPT
      reason: >-
        Core function.
      supported_by:
        - reference_id: PMID:21799911
          supporting_text: Ubiquitin ligase RNF146 regulates tankyrase and Axin 
            to promote Wnt signaling.
  - term:
      id: GO:0060090
      label: molecular adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:9601641
    review:
      summary: >-
        Foundational paper demonstrating AXIN1 as scaffold for the destruction complex.
      action: ACCEPT
      reason: >-
        Core function directly demonstrated.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Axin acts as a scaffold upon which APC, beta-catenin and
            GSK3 beta assemble"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27484798
    review:
      summary: >-
        GSKIP regulates beta-catenin through interactions with PKA and GSK3B; AXIN1-GSK3B
        context.
      action: ACCEPT
      reason: >-
        Destruction complex interactions.
      supported_by:
        - reference_id: PMID:27484798
          supporting_text: 2016 Aug 2. The A-Kinase Anchoring Protein (AKAP) 
            Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates 
            β-Catenin through Its Interactions with Both Protein Kinase A (PKA) 
            and GSK3β.
  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:22899650
    review:
      summary: >-
        LRRK2 functions as Wnt signaling scaffold bridging cytosolic proteins and
        LRP6;
        AXIN1 role in Wnt suppression demonstrated by loss-of-function.
      action: ACCEPT
      reason: >-
        Core function demonstrated by mutant phenotype.
      supported_by:
        - reference_id: PMID:22899650
          supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, 
            bridging cytosolic proteins and membrane-localized LRP6.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4641129
    review:
      summary: >-
        TAS from Reactome - AXIN ubiquitination by SMURF2.
      action: ACCEPT
      reason: >-
        Cytosolic context for AXIN1 regulation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4641256
    review:
      summary: >-
        TAS from Reactome - Ubiquitinated AXIN degradation.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3640861
    review:
      summary: >-
        TAS from Reactome - RNF146 ubiquitinates ADP-ribosylated AXIN.
      action: ACCEPT
      reason: >-
        Cytosolic context for AXIN1 regulation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3640872
    review:
      summary: >-
        TAS from Reactome - USP34 deubiquitinates AXIN1/AXIN2.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3640874
    review:
      summary: >-
        TAS from Reactome - Ub-RibC-AXIN degradation by proteasome.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3640844
    review:
      summary: >-
        TAS from Reactome - RNF146 binds RibC-AXIN:TNKS complex.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3640858
    review:
      summary: >-
        TAS from Reactome - Tankyrase ADP-ribosylates AXIN.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1504186
    review:
      summary: >-
        TAS from Reactome - DVL recruits GSK3beta:AXIN1 to receptor complex.
      action: ACCEPT
      reason: >-
        Cytosolic context for Wnt signaling.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-195251
    review:
      summary: >-
        TAS from Reactome - Assembly of the destruction complex.
      action: ACCEPT
      reason: >-
        Cytosolic localization for destruction complex assembly.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-201677
    review:
      summary: >-
        TAS from Reactome - Phosphorylation of LRP5/6 cytoplasmic domain.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-201685
    review:
      summary: >-
        TAS from Reactome - Beta-catenin release from destruction complex.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-3640862
    review:
      summary: >-
        TAS from Reactome - Tankyrase binds AXIN.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4641134
    review:
      summary: >-
        TAS from Reactome - SMURF2 binds AXIN.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4791278
    review:
      summary: >-
        TAS from Reactome - APC truncation mutants have impaired AXIN binding.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4827388
    review:
      summary: >-
        TAS from Reactome - CTNNB1 S45 mutants not phosphorylated by CK1alpha.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4839634
    review:
      summary: >-
        TAS from Reactome - CTNNB1 S33 mutants not phosphorylated by GSK3beta.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4839635
    review:
      summary: >-
        TAS from Reactome - CTNNB1 S37 mutants not phosphorylated by GSK3beta.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4839638
    review:
      summary: >-
        TAS from Reactome - CTNNB1 T41 mutants not phosphorylated by GSK3beta.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4839746
    review:
      summary: >-
        TAS from Reactome - Truncated AMER1 mutants destabilize destruction complex.
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5251555
    review:
      summary: >-
        TAS from Reactome - Expression of AXIN1 gene.
      action: ACCEPT
      reason: >-
        Gene expression context for cytosolic protein.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5368596
    review:
      summary: >-
        TAS from Reactome - WNT3A stimulates caveolin-dependent internalization.
      action: ACCEPT
      reason: >-
        Cytosolic context for Wnt signaling.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8932076
    review:
      summary: >-
        TAS from Reactome - AXIN1 gene expression regulated by ESR1 and RUNX1.
      action: ACCEPT
      reason: >-
        Gene expression context.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-1458902
    review:
      summary: >-
        TAS from Reactome - CK1gamma phosphorylates LRP5/6 (frog model).
      action: ACCEPT
      reason: >-
        Cytosolic context.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12192039
    review:
      summary: >-
        I-mfa domain proteins (MDFI, MDFIC) interact with AXIN1 and affect Wnt and
        JNK
        signaling.
      action: ACCEPT
      reason: >-
        Novel interactors affecting AXIN1 function.
      supported_by:
        - reference_id: PMID:12192039
          supporting_text: I-mfa domain proteins interact with Axin and affect 
            its regulation of the Wnt and c-Jun N-terminal kinase signaling 
            pathways.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:21383061
    review:
      summary: >-
        USP34 regulates AXIN1 stability; nuclear localization observed.
      action: ACCEPT
      reason: >-
        Nuclear localization documented.
      supported_by:
        - reference_id: PMID:21383061
          supporting_text: Mar 7. The ubiquitin-specific protease USP34 
            regulates axin stability and Wnt/β-catenin signaling.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:21383061
    review:
      summary: >-
        Cytoplasmic localization observed in USP34-AXIN1 study.
      action: ACCEPT
      reason: >-
        Primary localization.
      supported_by:
        - reference_id: PMID:21383061
          supporting_text: Mar 7. The ubiquitin-specific protease USP34 
            regulates axin stability and Wnt/β-catenin signaling.
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:19759537
    review:
      summary: >-
        AXIN1 binds tankyrase (TNKS/TNKS2) enzymes.
      action: ACCEPT
      reason: >-
        Important for AXIN1 regulation.
      supported_by:
        - reference_id: PMID:19759537
          supporting_text: Tankyrase inhibition stabilizes axin and antagonizes 
            Wnt signalling.
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:21383061
    review:
      summary: >-
        AXIN1 binds USP34 deubiquitinase.
      action: ACCEPT
      reason: >-
        Important for AXIN1 stability regulation.
      supported_by:
        - reference_id: PMID:21383061
          supporting_text: Mar 7. The ubiquitin-specific protease USP34 
            regulates axin stability and Wnt/β-catenin signaling.
  - term:
      id: GO:0019899
      label: enzyme binding
    evidence_type: IPI
    original_reference_id: PMID:21478859
    review:
      summary: >-
        AXIN1 binds RNF146 E3 ligase and tankyrase.
      action: ACCEPT
      reason: >-
        Important for AXIN1 regulation.
      supported_by:
        - reference_id: PMID:21478859
          supporting_text: RNF146 is a poly(ADP-ribose)-directed E3 ligase that 
            regulates axin degradation and Wnt signalling.
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:21478859
    review:
      summary: >-
        AXIN1 binds RNF146 E3 ubiquitin ligase.
      action: ACCEPT
      reason: >-
        Important for AXIN1 turnover regulation.
      supported_by:
        - reference_id: PMID:21478859
          supporting_text: RNF146 is a poly(ADP-ribose)-directed E3 ligase that 
            regulates axin degradation and Wnt signalling.
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:19038973
    review:
      summary: >-
        Perinuclear localization observed in human cumulus cells.
      action: ACCEPT
      reason: >-
        Localization pattern consistent with cytoplasmic function.
      supported_by:
        - reference_id: PMID:19038973
          supporting_text: Identification of WNT/beta-CATENIN signaling pathway 
            components in human cumulus cells.
  - term:
      id: GO:0071944
      label: cell periphery
    evidence_type: IDA
    original_reference_id: PMID:19038973
    review:
      summary: >-
        Cell periphery localization observed.
      action: ACCEPT
      reason: >-
        Consistent with membrane recruitment during Wnt signaling.
      supported_by:
        - reference_id: PMID:19038973
          supporting_text: Identification of WNT/beta-CATENIN signaling pathway 
            components in human cumulus cells.
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog. AXIN1 binds GSK3B and CK1 kinases.
      action: ACCEPT
      reason: >-
        Core function.
  - term:
      id: GO:2000060
      label: positive regulation of ubiquitin-dependent protein catabolic 
        process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog. AXIN1 promotes beta-catenin ubiquitination and degradation.
      action: ACCEPT
      reason: >-
        Core function.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:17569865
    review:
      summary: >-
        Wnt induces LRP6 signalosomes; AXIN1 cytoplasmic localization.
      action: ACCEPT
      reason: >-
        Primary localization.
      supported_by:
        - reference_id: PMID:17569865
          supporting_text: Wnt induces LRP6 signalosomes and promotes 
            dishevelled-dependent LRP6 phosphorylation.
  - term:
      id: GO:0065003
      label: protein-containing complex assembly
    evidence_type: IDA
    original_reference_id: PMID:16601693
    review:
      summary: >-
        AXIN1 promotes assembly of the Smad7-Arkadia complex for TGF-beta signaling.
      action: ACCEPT
      reason: >-
        AXIN1 scaffolding function in complex assembly.
      supported_by:
        - reference_id: PMID:16601693
          supporting_text: "Axin activates TGF-beta signaling by forming a multimeric
            complex consisting of Smad7 and ubiquitin E3 ligase Arkadia"
  - term:
      id: GO:0045732
      label: positive regulation of protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:9601641
    review:
      summary: >-
        AXIN1 promotes beta-catenin degradation.
      action: ACCEPT
      reason: >-
        Core function.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Overexpression of hAxin strongly promoted the downregulation
            of wild-type beta-catenin"
  - term:
      id: GO:0030877
      label: beta-catenin destruction complex
    evidence_type: IDA
    original_reference_id: PMID:16188939
    review:
      summary: >-
        IDA evidence for destruction complex membership from study of APC complexes.
      action: ACCEPT
      reason: >-
        Core complex membership.
      supported_by:
        - reference_id: PMID:16188939
          supporting_text: Sep 27. The adenomatous polyposis coli protein (APC) 
            exists in two distinct soluble complexes with different functions.
  - term:
      id: GO:0030877
      label: beta-catenin destruction complex
    evidence_type: IDA
    original_reference_id: PMID:19759537
    review:
      summary: >-
        Tankyrase inhibition stabilizes AXIN1 in the destruction complex.
      action: ACCEPT
      reason: >-
        Core complex membership.
      supported_by:
        - reference_id: PMID:19759537
          supporting_text: Tankyrase inhibition stabilizes axin and antagonizes 
            Wnt signalling.
  - term:
      id: GO:0045732
      label: positive regulation of protein catabolic process
    evidence_type: IC
    original_reference_id: PMID:16188939
    review:
      summary: >-
        Inferred from Curator based on destruction complex function.
      action: ACCEPT
      reason: >-
        Logical inference from scaffold role.
      supported_by:
        - reference_id: PMID:16188939
          supporting_text: Sep 27. The adenomatous polyposis coli protein (APC) 
            exists in two distinct soluble complexes with different functions.
  - term:
      id: GO:0070411
      label: I-SMAD binding
    evidence_type: IPI
    original_reference_id: PMID:16601693
    review:
      summary: >-
        AXIN1 binds SMAD7 in TGF-beta signaling context.
      action: ACCEPT
      reason: >-
        Experimentally validated.
      supported_by:
        - reference_id: PMID:16601693
          supporting_text: "Axin activates TGF-beta signaling by forming a multimeric
            complex consisting of Smad7"
  - term:
      id: GO:0008013
      label: beta-catenin binding
    evidence_type: IDA
    original_reference_id: PMID:10644691
    review:
      summary: >-
        PP2C dephosphorylates AXIN1; beta-catenin binding context demonstrated.
      action: ACCEPT
      reason: >-
        Core function.
      supported_by:
        - reference_id: PMID:10644691
          supporting_text: Protein phosphatase 2Calpha dephosphorylates axin and
            activates LEF-1-dependent transcription.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog. AXIN1 homodimerizes.
      action: ACCEPT
      reason: >-
        DIX domain-mediated self-association.
  - term:
      id: GO:0070016
      label: armadillo repeat domain binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        AXIN1 binds armadillo repeats of beta-catenin.
      action: ACCEPT
      reason: >-
        Structural basis for beta-catenin interaction.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17588722
    review:
      summary: >-
        Htid-1 (DNAJA3) interaction with APC; AXIN1 context.
      action: ACCEPT
      reason: >-
        APC complex interactions.
      supported_by:
        - reference_id: PMID:17588722
          supporting_text: 2007 Jun 2. Htid-1, the human homolog of the 
            Drosophila melanogaster l(2)tid tumor suppressor, defines a novel 
            physiological role of APC.
  - term:
      id: GO:0070411
      label: I-SMAD binding
    evidence_type: IPI
    original_reference_id: PMID:18593713
    review:
      summary: >-
        Smad7-AXIN1 interaction in cell adhesion context.
      action: ACCEPT
      reason: >-
        Validated interaction.
      supported_by:
        - reference_id: PMID:18593713
          supporting_text: "A Smad7-Axin interaction disassociates GSK-3beta and beta-catenin
            from Axin"
  - term:
      id: GO:0046332
      label: SMAD binding
    evidence_type: IPI
    original_reference_id: PMID:18593713
    review:
      summary: >-
        AXIN1 binds SMAD7.
      action: ACCEPT
      reason: >-
        Validated interaction.
      supported_by:
        - reference_id: PMID:18593713
          supporting_text: 2008 Jun 30. Smad7 stabilizes beta-catenin binding to
            E-cadherin complex and promotes cell-cell adhesion.
  - term:
      id: GO:0031410
      label: cytoplasmic vesicle
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary localization, not the primary site of function.
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog. DIX domain-mediated homodimerization.
      action: ACCEPT
      reason: >-
        Well-supported by experimental data.
  - term:
      id: GO:0046330
      label: positive regulation of JNK cascade
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        AXIN1 activates JNK signaling independently of Wnt.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary function of AXIN1 distinct from core Wnt pathway role.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9601641
    review:
      summary: >-
        Foundational paper demonstrating AXIN1 interactions with APC, beta-catenin,
        and GSK3B.
      action: ACCEPT
      reason: >-
        Multiple core interactions demonstrated.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Human Axin (hAxin) binds directly to beta-catenin, GSK3
            beta, and APC in vitro, and the endogenous proteins are found in a complex
            in cells"
  - term:
      id: GO:0030877
      label: beta-catenin destruction complex
    evidence_type: IDA
    original_reference_id: PMID:9601641
    review:
      summary: >-
        Foundational paper demonstrating AXIN1 as scaffold of the destruction complex.
      action: ACCEPT
      reason: >-
        Core complex membership demonstrated.
      supported_by:
        - reference_id: PMID:9601641
          supporting_text: "Axin acts as a scaffold upon which APC, beta-catenin and
            GSK3 beta assemble"
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:12072559
    review:
      summary: >-
        Nuclear localization observed in colon tissue.
      action: ACCEPT
      reason: >-
        AXIN1 can localize to nucleus.
      supported_by:
        - reference_id: PMID:12072559
          supporting_text: Subcellular distribution of Wnt pathway proteins in 
            normal and neoplastic colon.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:12072559
    review:
      summary: >-
        Cytoplasmic localization in colon tissue.
      action: ACCEPT
      reason: >-
        Primary localization.
      supported_by:
        - reference_id: PMID:12072559
          supporting_text: Subcellular distribution of Wnt pathway proteins in 
            normal and neoplastic colon.
  - term:
      id: GO:0016328
      label: lateral plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:12072559
    review:
      summary: >-
        Lateral plasma membrane localization observed in colon epithelium.
      action: ACCEPT
      reason: >-
        Tissue-specific membrane localization pattern.
      supported_by:
        - reference_id: PMID:12072559
          supporting_text: Subcellular distribution of Wnt pathway proteins in 
            normal and neoplastic colon.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - 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:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:9601641
    title: Downregulation of beta-catenin by human Axin and its association with
      the APC tumor suppressor, beta-catenin and GSK3 beta.
    findings:
      - statement: AXIN1 acts as scaffold for destruction complex assembly
      - statement: AXIN1 promotes beta-catenin phosphorylation by GSK3B
      - statement: AXIN1 binds APC, beta-catenin, and GSK3B directly
  - id: PMID:10644691
    title: Protein phosphatase 2Calpha dephosphorylates axin and activates 
      LEF-1-dependent transcription.
    findings:
      - statement: PP2C dephosphorylates AXIN1
      - statement: AXIN1 represses LEF-1-dependent transcription
      - statement: AXIN1 is a negative regulator of Wnt signaling
  - id: PMID:16601693
    title: Axin is a scaffold protein in TGF-beta signaling that promotes 
      degradation of Smad7 by Arkadia.
    findings:
      - statement: AXIN1 activates TGF-beta signaling
      - statement: AXIN1 forms complex with Smad7 and Arkadia (RNF111)
      - statement: AXIN1 promotes Smad7 ubiquitination and degradation
  - id: PMID:18593713
    title: Smad7 stabilizes beta-catenin binding to E-cadherin complex and 
      promotes cell-cell adhesion.
    findings:
      - statement: Smad7-AXIN1 interaction affects destruction complex
      - statement: Smad7 binding disassociates GSK3B and beta-catenin from AXIN1
  - id: PMID:10481074
    title: A GSK3-binding peptide from FRAT1 selectively inhibits the 
      GSK3-catalysed phosphorylation of axin and beta-catenin.
    findings: []
  - id: PMID:10811618
    title: Structural basis of the Axin-adenomatous polyposis coli interaction.
    findings: []
  - id: PMID:11738041
    title: The structure of phosphorylated GSK-3beta complexed with a peptide, 
      FRATtide, that inhibits beta-catenin phosphorylation.
    findings: []
  - id: PMID:16169070
    title: "A human protein-protein interaction network: a resource for annotating
      the proteome."
    findings: []
  - id: PMID:16293619
    title: Beta-catenin-ligand interactions.
    findings: []
  - id: PMID:17318175
    title: Protein phosphatase 1 regulates assembly and function of the 
      beta-catenin degradation complex.
    findings: []
  - id: PMID:17318191
    title: Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through 
      its tyrosine phosphorylation.
    findings: []
  - id: PMID:17510365
    title: Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin 
      signaling.
    findings: []
  - id: PMID:17601533
    title: Two functionally distinct Axin-like proteins regulate canonical Wnt 
      signaling in C. elegans.
    findings: []
  - id: PMID:18786926
    title: Identification of a link between the SAMP repeats of adenomatous 
      polyposis coli tumor suppressor and the Src homology 3 domain of DDEF.
    findings: []
  - id: PMID:19131971
    title: The Axin1 scaffold protein promotes formation of a degradation 
      complex for c-Myc.
    findings: []
  - id: PMID:19166851
    title: Kaiso is a bimodal modulator for Wnt/beta-catenin signaling.
    findings: []
  - id: PMID:19202075
    title: Beta-arrestin links endothelin A receptor to beta-catenin signaling.
    findings: []
  - id: PMID:19249679
    title: Oncogenic function of ATDC in pancreatic cancer through Wnt pathway 
      activation and beta-catenin stabilization.
    findings: []
  - id: PMID:19303846
    title: Disrupted in schizophrenia 1 regulates neuronal progenitor 
      proliferation via modulation of GSK3beta/beta-catenin signaling.
    findings: []
  - id: PMID:19390532
    title: Axin localizes to the centrosome and is involved in microtubule 
      nucleation.
    findings: []
  - id: PMID:19759537
    title: Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.
    findings: []
  - id: PMID:20080667
    title: Role of DAB2IP in modulating epithelial-to-mesenchymal transition and
      prostate cancer metastasis.
    findings: []
  - id: PMID:21057547
    title: AXIN is an essential co-activator for the promyelocytic leukemia 
      protein in p53 activation.
    findings: []
  - id: PMID:21242974
    title: Methylation by protein arginine methyltransferase 1 increases 
      stability of Axin, a negative regulator of Wnt signaling.
    findings: []
  - id: PMID:21245303
    title: Dishevelled interacts with the DIX domain polymerization interface of
      Axin to interfere with its function in down-regulating β-catenin.
    findings: []
  - id: PMID:21988832
    title: Toward an understanding of the protein interaction network of the 
      human liver.
    findings: []
  - id: PMID:22153077
    title: Structural basis and sequence rules for substrate recognition by 
      Tankyrase explain the basis for cherubism disease.
    findings: []
  - id: PMID:22682247
    title: Wnt signaling through inhibition of β-catenin degradation in an 
      intact Axin1 complex.
    findings: []
  - id: PMID:22773187
    title: Dual functions of DP1 promote biphasic Wnt-on and Wnt-off states 
      during anteroposterior neural patterning.
    findings: []
  - id: PMID:23455922
    title: Interlaboratory reproducibility of large-scale human protein-complex 
      analysis by standardized AP-MS.
    findings: []
  - id: PMID:23602568
    title: The protein interaction landscape of the human CMGC kinase group.
    findings: []
  - id: PMID:24976009
    title: YAP/TAZ incorporation in the β-catenin destruction complex 
      orchestrates the Wnt response.
    findings: []
  - id: PMID:25241761
    title: Using an in situ proximity ligation assay to systematically profile 
      endogenous protein-protein interactions in a pathway network.
    findings: []
  - id: PMID:25873176
    title: TGIF governs a feed-forward network that empowers Wnt signaling to 
      drive mammary tumorigenesis.
    findings: []
  - id: PMID:26496610
    title: Human interactome in three quantitative dimensions.
    findings: []
  - id: PMID:26871637
    title: Widespread Expansion of Protein Interaction Capabilities by 
      Alternative Splicing.
    findings: []
  - id: PMID:27098453
    title: WDR26 is a new partner of Axin1 in the canonical Wnt signaling 
      pathway.
    findings: []
  - id: PMID:29568061
    title: An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping 
      of protein interactions and subcellular localizations.
    findings: []
  - id: PMID:32707033
    title: Kinase Interaction Network Expands Functional and Disease Roles of 
      Human Kinases.
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:35271311
    title: OpenCell Endogenous tagging for the cartography of human cellular 
      organization.
    findings: []
  - id: PMID:21087614
    title: Critical scaffolding regions of the tumor suppressor Axin1 are 
      natively unfolded.
    findings: []
  - id: PMID:28546513
    title: The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through
      mediating Wnt-induced Axin degradation.
    findings: []
  - id: PMID:28829046
    title: Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling 
      and colorectal tumorigenesis.
    findings: []
  - id: PMID:21799911
    title: Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt 
      signaling.
    findings: []
  - id: PMID:27484798
    title: The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β 
      Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions 
      with Both Protein Kinase A (PKA) and GSK3β.
    findings: []
  - id: PMID:22899650
    title: LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic 
      proteins and membrane-localized LRP6.
    findings: []
  - id: PMID:12192039
    title: I-mfa domain proteins interact with Axin and affect its regulation of
      the Wnt and c-Jun N-terminal kinase signaling pathways.
    findings: []
  - id: PMID:21383061
    title: The ubiquitin-specific protease USP34 regulates axin stability and 
      Wnt/β-catenin signaling.
    findings: []
  - id: PMID:21478859
    title: RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin 
      degradation and Wnt signalling.
    findings: []
  - id: PMID:19038973
    title: Identification of WNT/beta-CATENIN signaling pathway components in 
      human cumulus cells.
    findings: []
  - id: PMID:17569865
    title: Wnt induces LRP6 signalosomes.
    findings: []
  - id: PMID:16188939
    title: The adenomatous polyposis coli protein (APC) exists in two distinct 
      soluble complexes with different functions.
    findings: []
  - id: PMID:17588722
    title: Htid-1, the human homolog of the Drosophila melanogaster l(2)tid 
      tumor suppressor, defines a novel physiological role of APC.
    findings: []
  - id: PMID:12072559
    title: Subcellular distribution of Wnt pathway proteins in normal and 
      neoplastic colon.
    findings: []
  - id: Reactome:R-HSA-195275
    title: Phosphorylation of APC in the destruction complex
    findings: []
  - id: Reactome:R-HSA-195280
    title: Dissociation of beta-catenin from Axin and association with 
      phospho-APC
    findings: []
  - id: Reactome:R-HSA-195283
    title: GSK3 phosphorylation of beta-catenin at Ser37
    findings: []
  - id: Reactome:R-HSA-195287
    title: GSK3 phosphorylation of beta-catenin at Thr41
    findings: []
  - id: Reactome:R-HSA-195300
    title: GSK3 phosphorylation of beta-catenin at Ser33
    findings: []
  - id: Reactome:R-HSA-195304
    title: Association of beta-catenin with destruction complex
    findings: []
  - id: Reactome:R-HSA-195318
    title: CK1alpha phosphorylation of beta-catenin at Ser45
    findings: []
  - id: Reactome:R-HSA-2130279
    title: Beta-catenin association with SCF(beta-TrCP) complex
    findings: []
  - id: Reactome:R-HSA-2130282
    title: Degradation of ubiquitinated beta-catenin
    findings: []
  - id: Reactome:R-HSA-2130286
    title: Multi-ubiquitination of phospho-beta-catenin
    findings: []
  - id: Reactome:R-HSA-5229343
    title: AXIN phosphorylation in destruction complex
    findings: []
  - id: Reactome:R-HSA-5339713
    title: Misspliced GSK3beta mutants stabilize beta-catenin
    findings: []
  - id: Reactome:R-HSA-4839734
    title: AXIN mutants destabilize destruction complex
    findings: []
  - id: Reactome:R-HSA-4641129
    title: AXIN ubiquitination by SMURF2
    findings: []
  - id: Reactome:R-HSA-4641256
    title: Ubiquitinated AXIN degradation
    findings: []
  - id: Reactome:R-HSA-3640861
    title: RNF146 ubiquitinates ADP-ribosylated AXIN
    findings: []
  - id: Reactome:R-HSA-3640872
    title: USP34 deubiquitinates AXIN1/AXIN2
    findings: []
  - id: Reactome:R-HSA-3640874
    title: Ub-RibC-AXIN degradation by proteasome
    findings: []
  - id: Reactome:R-HSA-3640844
    title: RNF146 binds RibC-AXIN:TNKS complex
    findings: []
  - id: Reactome:R-HSA-3640858
    title: Tankyrase ADP-ribosylates AXIN
    findings: []
  - id: Reactome:R-HSA-1504186
    title: DVL recruits GSK3beta:AXIN1 to receptor complex
    findings: []
  - id: Reactome:R-HSA-195251
    title: Assembly of the destruction complex
    findings: []
  - id: Reactome:R-HSA-201677
    title: Phosphorylation of LRP5/6 cytoplasmic domain
    findings: []
  - id: Reactome:R-HSA-201685
    title: Beta-catenin release from destruction complex
    findings: []
  - id: Reactome:R-HSA-3640862
    title: Tankyrase binds AXIN
    findings: []
  - id: Reactome:R-HSA-4641134
    title: SMURF2 binds AXIN
    findings: []
  - id: Reactome:R-HSA-4791278
    title: APC truncation mutants have impaired AXIN binding
    findings: []
  - id: Reactome:R-HSA-4827388
    title: CTNNB1 S45 mutants not phosphorylated by CK1alpha
    findings: []
  - id: Reactome:R-HSA-4839634
    title: CTNNB1 S33 mutants not phosphorylated by GSK3beta
    findings: []
  - id: Reactome:R-HSA-4839635
    title: CTNNB1 S37 mutants not phosphorylated by GSK3beta
    findings: []
  - id: Reactome:R-HSA-4839638
    title: CTNNB1 T41 mutants not phosphorylated by GSK3beta
    findings: []
  - id: Reactome:R-HSA-4839746
    title: Truncated AMER1 mutants destabilize destruction complex
    findings: []
  - id: Reactome:R-HSA-5251555
    title: Expression of AXIN1 gene
    findings: []
  - id: Reactome:R-HSA-5368596
    title: WNT3A stimulates caveolin-dependent internalization
    findings: []
  - id: Reactome:R-HSA-8932076
    title: AXIN1 gene expression regulated by ESR1 and RUNX1
    findings: []
  - id: Reactome:R-NUL-1458902
    title: CK1gamma phosphorylates LRP5/6 (frog model)
    findings: []
  - id: file:human/AXIN1/AXIN1-deep-research-falcon.md
    title: Deep research report on AXIN1
    findings: []
core_functions:
  - description: >-
      THE core function of AXIN1. As the central scaffold of the beta-catenin destruction
      complex, AXIN1 coordinates CK1 and GSK3B phosphorylation of beta-catenin, leading
      to its ubiquitination and degradation, thereby suppressing Wnt target gene
      transcription.
    molecular_function:
      id: GO:0060090
      label: molecular adaptor activity
    directly_involved_in:
      - id: GO:0090090
        label: negative regulation of canonical Wnt signaling pathway
    in_complex:
      id: GO:0030877
      label: beta-catenin destruction complex
    locations:
      - id: GO:0005829
        label: cytosol
    supported_by:
      - reference_id: PMID:9601641
        supporting_text: "Axin acts as a scaffold upon which APC, beta-catenin and
          GSK3 beta assemble to coordinate the regulation of beta-catenin signaling."
proposed_new_terms: []
suggested_questions:
  - question: >-
      How does AXIN1 condensate formation (degradasomes) contribute to the efficiency
      of beta-catenin destruction complex function?
  - question: >-
      What is the relative contribution of AXIN1 versus AXIN2 to Wnt pathway regulation
      in different tissue contexts?
suggested_experiments: []