id: Q8IUQ4
gene_symbol: SIAH1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SIAH1 (seven in absentia homolog 1) is a RING-type E3 ubiquitin-protein ligase
  (EC 2.3.2.27) that catalyzes ubiquitination and subsequent proteasomal
  degradation of a broad set of substrates. It is built from an N-terminal
  RING-type zinc finger that recruits a ubiquitin-charged E2 conjugating enzyme
  (e.g. UBE2D1, UBE2E2, UBE2I, UBE2L6) and a C-terminal SIAH-type substrate-binding
  domain containing additional zinc fingers that recognizes substrate degrons,
  typically a Pro-x-Ala-x-Val-x-Pro (PxAxVxP) motif. SIAH1 functions as a
  homodimer (and can heterodimerize with the closely related SIAH2), and can act
  either by binding substrates directly or as the RING subunit of larger
  multiprotein E3 complexes. Its best-characterized substrates and pathways
  include: DCC (the netrin receptor deleted in colorectal cancer), establishing a
  role in nervous-system development and axon guidance; beta-catenin (CTNNB1),
  which SIAH1 degrades via a p53-inducible, GSK3beta/beta-TrCP-independent pathway
  acting with APC, the adaptor SIP/CACYBP, SKP1 and Ebi/TBL1X as part of a
  beta-catenin destruction complex; AXIN1, whose Wnt-induced degradation by SIAH1
  provides a feed-forward boost to canonical Wnt/beta-catenin signaling;
  alpha-synuclein (SNCA, monoubiquitylation) and synphilin-1 (SNCAIP), linking
  SIAH1 to Lewy-body/inclusion formation in Parkinson disease; XIAP (via the ARTS
  adaptor) and other apoptotic regulators, promoting intrinsic apoptosis; the
  kinase HIPK2 (constitutive, DAZAP2-assisted degradation in the DNA-damage/p53
  response); and the prolyl hydroxylases EGLN2/EGLN3, coupling SIAH1 to the
  hypoxic/unfolded-protein response. SIAH1 is predominantly cytoplasmic with a
  partial nuclear pool, is itself p53-inducible, and contributes to apoptosis,
  tumor suppression, transcriptional regulation, and Wnt signaling.
alternative_products:
- name: '1'
  id: Q8IUQ4-1
- name: '2'
  id: Q8IUQ4-2
  sequence_note: VSP_010166
- name: 3 (Siah-1S)
  id: Q8IUQ4-3
  sequence_note: VSP_029210, VSP_029211
existing_annotations:
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of proteasome-mediated ubiquitin-dependent protein catabolism, the core biological process of SIAH1, which targets numerous substrates for proteasomal degradation.
    action: ACCEPT
    reason: Core biological process; SIAH1 ubiquitinates substrates (DCC, beta-catenin, XIAP, HIPK2, AXIN1) for proteasomal degradation, demonstrated by proteasome-inhibitor-sensitive degradation assays.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: Proteasome inhibitors blocked the effects of Sina/Siah on DCC
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of ubiquitin protein ligase activity, the core molecular function of SIAH1 as a genuine RING-type E3 ligase.
    action: ACCEPT
    reason: Core molecular function; SIAH1 is a catalytic RING E3 ligase, corroborated by experimental EXP/IDA evidence.
    supported_by:
    - reference_id: PMID:19224863
      supporting_text: the ubiquitin-protein isopeptide ligase SIAH
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference that SIAH1 is active in the cytoplasm, its dominant subcellular compartment and site of action on most substrates.
    action: ACCEPT
    reason: Core localization; SIAH1 is predominantly cytoplasmic, where it associates with and degrades substrates such as DCC.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of E2 (ubiquitin-conjugating enzyme) binding, a defining feature of the SIAH1 RING domain and essential to its catalytic mechanism.
    action: ACCEPT
    reason: Core molecular function; SIAH1 binds E2 enzymes (Ubcs) through its N-terminal RING region, and a Ubc-binding-deficient mutant cannot degrade substrate.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins interacted with ubiquitin-conjugating enzymes (Ubcs)
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of nuclear localization. SIAH1 has a real but secondary nuclear pool where it acts on nuclear substrates (e.g. HIPK2, transcription factors).
    action: KEEP_AS_NON_CORE
    reason: Real secondary localization (nuclear substrates such as HIPK2), but the dominant active compartment is cytoplasmic.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of cytoplasmic localization, the dominant compartment of SIAH1.
    action: ACCEPT
    reason: Core localization; redundant with the IBA cytoplasm and TAS cytoplasm annotations.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic assignment of ubiquitin-dependent protein catabolism, a parent of the specific proteasome-mediated catabolic process SIAH1 mediates.
    action: KEEP_AS_NON_CORE
    reason: Correct but more generic; the specific proteasome-mediated ubiquitin-dependent catabolic process annotation better captures the role.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of zinc ion binding; SIAH1 has a RING-type zinc finger and additional SIAH-type zinc fingers that coordinate zinc.
    action: ACCEPT
    reason: Structurally required; the RING and SIAH-type zinc fingers coordinate zinc, essential for the fold and catalysis.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: ZN_FING
- term:
    id: GO:0060070
    label: canonical Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of involvement in canonical Wnt signaling. SIAH1 both degrades beta-catenin (negative) and degrades AXIN1 (positive, feed-forward), so it is a genuine but pleiotropic regulator of this pathway.
    action: KEEP_AS_NON_CORE
    reason: SIAH1 genuinely participates in canonical Wnt signaling (via beta-catenin and AXIN1 degradation), but this is a downstream pathway outcome of its ligase activity rather than its core molecular function.
    supported_by:
    - reference_id: PMID:28546513
      supporting_text: SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/β-catenin signaling
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: Enzyme Commission-based electronic assignment of ubiquitin protein ligase activity (EC 2.3.2.27), the core catalytic molecular function.
    action: ACCEPT
    reason: Core molecular function; redundant with the IBA/EXP/IDA ligase activity annotations.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: EC=2.3.2.27
- term:
    id: GO:1990000
    label: amyloid fibril formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of amyloid fibril formation, reflecting the alpha-synuclein/synphilin-1 context. This describes the aggregation behavior of SIAH1 substrates (Lewy-body inclusions), not an intrinsic SIAH1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: SIAH1 monoubiquitylates alpha-synuclein and ubiquitinates synphilin-1 and influences inclusion formation, but amyloid fibril formation is the substrate's property; assigning it as a SIAH1 process is an over-annotation.
    supported_by:
    - reference_id: PMID:19224863
      supporting_text: SIAH also increases the formation of synphilin-1A inclusions
- term:
    id: GO:2001233
    label: regulation of apoptotic signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of regulation of apoptotic signaling. SIAH1 promotes apoptosis (e.g. via XIAP degradation), a downstream process of its ligase activity.
    action: KEEP_AS_NON_CORE
    reason: SIAH1 genuinely regulates apoptosis (XIAP degradation, POSH/JNK), but this is a downstream biological outcome rather than its core function.
    supported_by:
    - reference_id: PMID:21185211
      supporting_text: ARTS interacts with the E3 ligase Siah-1 (seven in absentia homolog 1) to induce ubiquitination and degradation of XIAP
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11483518
  qualifier: enables
  review:
    summary: Interaction with BOB.1/OBF.1 (POU2AF1), whose stability SIAH regulates. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction (BOB.1/OBF.1) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16230351
  qualifier: enables
  review:
    summary: Interaction with the scaffold protein POSH (promotes JNK activation and apoptosis). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction (POSH) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19549727
  qualifier: enables
  review:
    summary: Interaction from the human E2 ubiquitin-conjugating enzyme network (E2 binding). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction (E2 enzymes, central to the RING mechanism) but bare protein binding is uninformative; the ubiquitin conjugating enzyme binding term is more specific.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21078624
  qualifier: enables
  review:
    summary: Interaction from an expanded ataxia interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21185211
  qualifier: enables
  review:
    summary: Interaction with XIAP/ARTS in the XIAP-degradation pathway. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real, functionally important interactions (ARTS/XIAP) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:21185211
      supporting_text: ARTS interacts with the E3 ligase Siah-1 (seven in absentia homolog 1) to induce ubiquitination and degradation of XIAP
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: High-throughput interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21878328
  qualifier: enables
  review:
    summary: Interaction with the hepatitis B viral X protein (HBx), a SIAH1 substrate. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real substrate interaction (HBx) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: Human liver protein interaction network interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23840749
  qualifier: enables
  review:
    summary: Interaction from a mu-opioid receptor interacting-protein screen. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: Self-association evidence; SIAH1 functions as a homodimer (and can heterodimerize with SIAH2). A real, informative homotypic interaction.
    action: KEEP_AS_NON_CORE
    reason: SIAH1 genuinely homodimerizes, which is required for its function, but this is a structural property supporting rather than defining the core ligase activity.
    supported_by:
    - reference_id: PMID:22493164
      supporting_text: dimeric E3-RING interactions
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22493164
  qualifier: enables
  review:
    summary: Systematic dimeric E3-RING interaction analysis; SIAH1 self-associates (homodimer). A real homotypic interaction.
    action: KEEP_AS_NON_CORE
    reason: SIAH1 self-associates (homodimer); supports its function but is not the core catalytic role.
    supported_by:
    - reference_id: PMID:22493164
      supporting_text: dimeric E3-RING interactions
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome self-interaction (SIAH1 homodimerization).
    action: KEEP_AS_NON_CORE
    reason: SIAH1 self-associates (homodimer); supports its function but is not the core catalytic role.
    supported_by:
    - reference_id: PMID:22493164
      supporting_text: dimeric E3-RING interactions
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara) ubiquitin-protein transferase activity, the core catalytic molecular function of SIAH1.
    action: ACCEPT
    reason: Core molecular function; synonymous with ubiquitin protein ligase activity for this catalytic RING E3.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: EC=2.3.2.27
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-transferred (Ensembl Compara) early endosome localization. Not strongly supported by primary human SIAH1 literature, which emphasizes cytoplasmic and nuclear pools.
    action: KEEP_AS_NON_CORE
    reason: A minor, ortholog-transferred localization with weak support in the human literature; retained cautiously as non-core rather than removed, as endosomal pools cannot be excluded.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-transferred (Ensembl Compara) cytosolic localization, consistent with the dominant cytoplasmic compartment of SIAH1.
    action: ACCEPT
    reason: Core localization; consistent with the cytoplasmic/cytosolic site of action.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0031648
    label: protein destabilization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara) protein destabilization, a consequence of SIAH1-mediated ubiquitination and degradation of its substrates.
    action: KEEP_AS_NON_CORE
    reason: Correct as a consequence of SIAH1's degradative activity, but the catabolic-process and ligase-activity annotations capture the mechanism more directly.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway
- term:
    id: GO:0051402
    label: neuron apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transferred (Ensembl Compara) involvement in neuron apoptosis, consistent with SIAH1's pro-apoptotic role and Parkinson-disease-related substrates.
    action: KEEP_AS_NON_CORE
    reason: A downstream, context-specific (neuronal) process of SIAH1's apoptosis-promoting activity, not its core function.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived general protein ubiquitination process, the core catalytic process of SIAH1 (here at a generic level).
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific proteasome-mediated catabolic process annotation better captures the role.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (Human Protein Atlas) evidence of nucleoplasmic localization; the real but secondary nuclear pool of SIAH1.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported nuclear pool (consistent with nuclear substrates such as HIPK2) but secondary to the dominant cytoplasmic compartment.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:19224863
  qualifier: enables
  review:
    summary: Experimental evidence that SIAH is a ubiquitin-protein (isopeptide) ligase that ubiquitylates alpha-synuclein and synphilin-1. Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; SIAH1 is a catalytic RING E3 ligase.
    supported_by:
    - reference_id: PMID:19224863
      supporting_text: the ubiquitin-protein isopeptide ligase SIAH
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5660753
  qualifier: enables
  review:
    summary: Reactome curation (SIAH1:UBE2L6:Ubiquitin ubiquitinates SNCA) of ubiquitin-protein transferase activity, the core catalytic molecular function.
    action: ACCEPT
    reason: Core molecular function; SIAH1 transfers ubiquitin (with E2 UBE2L6) to its substrate SNCA. Synonymous with ubiquitin protein ligase activity.
    supported_by:
    - reference_id: PMID:19224863
      supporting_text: ubiquitin-ligase that ubiquitylates alpha-synuclein and synphilin-1
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5667107
  qualifier: enables
  review:
    summary: Reactome curation (SIAH1, SIAH2 ubiquitinate SNCAIP) of ubiquitin-protein transferase activity, the core catalytic molecular function.
    action: ACCEPT
    reason: Core molecular function; SIAH1 transfers ubiquitin to synphilin-1 (SNCAIP). Synonymous with ubiquitin protein ligase activity.
    supported_by:
    - reference_id: PMID:19224863
      supporting_text: ubiquitin-ligase that ubiquitylates alpha-synuclein and synphilin-1
- term:
    id: GO:1990000
    label: amyloid fibril formation
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-977225
  qualifier: involved_in
  review:
    summary: Reactome curation placing SIAH1 in the amyloid-fiber-formation pathway via its alpha-synuclein context. This is the substrate's aggregation behavior, not an intrinsic SIAH1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: SIAH1 monoubiquitylates alpha-synuclein and influences inclusion formation, but amyloid fibril formation is a property of the substrate; assigning it as a SIAH1 process is an over-annotation (though Reactome curates SIAH1 within the SNCA amyloid pathway).
    supported_by:
    - reference_id: PMID:19224863
      supporting_text: SIAH also increases the formation of synphilin-1A inclusions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33591310
  qualifier: enables
  review:
    summary: Interaction with HIPK2/DAZAP2 in the DNA-damage/p53 response. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real, functionally important interactions (HIPK2/DAZAP2) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:33591310
      supporting_text: DAZAP2 stimulates HIPK2 polyubiquitination and degradation through interplay with the ubiquitin ligase SIAH1
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:33591310
  qualifier: involved_in
  review:
    summary: Direct evidence that SIAH1 drives polyubiquitination and degradation of HIPK2 (DAZAP2-assisted) in the DNA-damage/p53 response. Core biological process.
    action: ACCEPT
    reason: Core biological process directly demonstrated; SIAH1 targets HIPK2 for proteasomal degradation.
    supported_by:
    - reference_id: PMID:33591310
      supporting_text: DAZAP2 stimulates HIPK2 polyubiquitination and degradation through interplay with the ubiquitin ligase SIAH1
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:28546513
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that SIAH1 promotes ubiquitination and proteasomal degradation of AXIN1 (SIAH1 knockout blocks Wnt-induced Axin ubiquitination). Core biological process.
    action: ACCEPT
    reason: Core biological process; SIAH1 targets AXIN1 for proteasomal degradation, demonstrated by knockout.
    supported_by:
    - reference_id: PMID:28546513
      supporting_text: SIAH proteins promote the ubiquitination and proteasomal degradation of Axin
- term:
    id: GO:0060070
    label: canonical Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:28546513
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that SIAH1 promotes Wnt/beta-catenin signaling by degrading AXIN1 (a feed-forward mechanism); SIAH1 knockout attenuates Wnt-induced beta-catenin stabilization.
    action: KEEP_AS_NON_CORE
    reason: SIAH1 genuinely participates in canonical Wnt signaling (positive, via AXIN1 degradation), but this is a downstream pathway outcome of its ligase activity rather than its core molecular function.
    supported_by:
    - reference_id: PMID:28546513
      supporting_text: Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced β-catenin stabilization
- term:
    id: GO:0060070
    label: canonical Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:32430360
  qualifier: involved_in
  review:
    summary: De novo SIAH1 variants associated with developmental delay also affect Wnt signaling; mutant-phenotype evidence linking SIAH1 to the canonical Wnt pathway.
    action: KEEP_AS_NON_CORE
    reason: Supports SIAH1 involvement in canonical Wnt signaling (disease-variant evidence), but this is a downstream pathway role rather than the core function.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:28546513
  qualifier: enables
  review:
    summary: Mutant-phenotype evidence (SIAH1 knockout abolishes Wnt-induced Axin ubiquitination) supporting SIAH1 ubiquitin protein ligase activity. Core molecular function.
    action: ACCEPT
    reason: Core molecular function; SIAH1 ligase activity is required for AXIN1 ubiquitination.
    supported_by:
    - reference_id: PMID:28546513
      supporting_text: Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28546513
  qualifier: enables
  review:
    summary: Interaction with AXIN1 (a SIAH1 substrate) via a VxP motif. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real substrate interaction (AXIN1) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:28546513
      supporting_text: SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:23001567
  qualifier: enables
  review:
    summary: Direct evidence that SIAH1 (Siah-1) mediates ubiquitination of the transcription factor Jade-1. Core molecular function.
    action: ACCEPT
    reason: Core molecular function directly demonstrated; SIAH1 ubiquitinates Jade-1.
    supported_by:
    - reference_id: PMID:23001567
      supporting_text: Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1
- term:
    id: GO:2001244
    label: positive regulation of intrinsic apoptotic signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:21185211
  qualifier: involved_in
  review:
    summary: SIAH1 (with the ARTS adaptor) promotes XIAP degradation, lowering the apoptotic threshold; cells lacking Siah contain higher XIAP. A pro-apoptotic downstream role.
    action: KEEP_AS_NON_CORE
    reason: SIAH1 genuinely promotes intrinsic apoptosis (via XIAP degradation), but this is a downstream biological process of its ligase activity rather than its core function.
    supported_by:
    - reference_id: PMID:21185211
      supporting_text: Cells lacking either Siah or ARTS contain higher steady-state levels of XIAP
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:23001567
  qualifier: acts_upstream_of_or_within
  review:
    summary: Direct evidence that SIAH1 mediates ubiquitin-dependent catabolism of Jade-1. Core biological process (generic level).
    action: KEEP_AS_NON_CORE
    reason: Correct but the more specific proteasome-mediated catabolic process annotation better captures the role; retained as non-core given the generic parent term.
    supported_by:
    - reference_id: PMID:23001567
      supporting_text: Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-374665
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (DCC interaction with SIAH1). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization where SIAH1 binds and degrades DCC.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5658092
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (SIAH1, SIAH2 bind SNCAIP). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization where SIAH1 acts on synphilin-1.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5658496
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (SIAH1:UBE2L6:Ubiquitin binds SNCA). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization where SIAH1 acts on alpha-synuclein.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5660753
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (SIAH1:UBE2L6:Ubiquitin ubiquitinates SNCA). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5660757
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (Ub-SNCA dissociates from the conjugating enzyme). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5667107
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (SIAH1, SIAH2 ubiquitinate SNCAIP). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct core cytosolic localization.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (generic transfer of Ub from E2 to substrate). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct cytosolic compartment for the ubiquitination reaction; from generic ubiquitination-pathway context.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct cytosolic compartment; from generic ubiquitination-pathway context.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct cytosolic compartment; from generic ubiquitination-pathway context.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub complex). Consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct cytosolic compartment; from generic ubiquitination-pathway context.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IMP
  original_reference_id: PMID:21185211
  qualifier: enables
  review:
    summary: Mutant-phenotype evidence supporting SIAH1 ubiquitin-protein transferase activity in the ARTS-mediated XIAP degradation pathway. Core molecular function.
    action: ACCEPT
    reason: Core molecular function; SIAH1 ligase activity drives XIAP ubiquitination/degradation.
    supported_by:
    - reference_id: PMID:21185211
      supporting_text: ARTS interacts with the E3 ligase Siah-1 (seven in absentia homolog 1) to induce ubiquitination and degradation of XIAP
- term:
    id: GO:0043065
    label: positive regulation of apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:21185211
  qualifier: involved_in
  review:
    summary: SIAH1 promotes apoptosis by degrading XIAP (via ARTS). A downstream pro-apoptotic role of its ligase activity.
    action: KEEP_AS_NON_CORE
    reason: SIAH1 genuinely promotes apoptosis (XIAP degradation), but this is a downstream biological process rather than the core molecular function.
    supported_by:
    - reference_id: PMID:21185211
      supporting_text: ARTS serves as an adaptor to bridge Siah-1 to XIAP, targeting it for destruction
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based assignment of nuclear localization; the real but secondary nuclear pool of SIAH1.
    action: KEEP_AS_NON_CORE
    reason: Real secondary localization (nuclear substrates such as HIPK2), but the dominant active compartment is cytoplasmic. Redundant with the IEA nucleus and IDA nucleoplasm annotations.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0051402
    label: neuron apoptotic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity-based assignment of involvement in neuron apoptosis, consistent with SIAH1's pro-apoptotic role and Parkinson-related substrates.
    action: KEEP_AS_NON_CORE
    reason: A downstream, neuronal-context process of SIAH1's apoptosis-promoting activity, not its core function.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity-based assignment of ubiquitin-protein transferase activity, the core catalytic molecular function of SIAH1.
    action: ACCEPT
    reason: Core molecular function; redundant with the experimental ligase/transferase annotations.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: EC=2.3.2.27
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity-based assignment of ubiquitin-dependent protein catabolism, a parent of the specific proteasome-mediated catabolic process SIAH1 mediates.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific proteasome-mediated catabolic process annotation better captures the role.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity-based assignment of zinc ion binding; SIAH1 has a RING-type zinc finger and SIAH-type zinc fingers.
    action: ACCEPT
    reason: Structurally required; the RING and SIAH-type zinc fingers coordinate zinc.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: ZN_FING
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity-based assignment of proteasome-mediated ubiquitin-dependent catabolism, the core biological process of SIAH1.
    action: ACCEPT
    reason: Core biological process; redundant with the IBA/IDA/IMP catabolic-process annotations.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: Proteasome inhibitors blocked the effects of Sina/Siah on DCC
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16085652
  qualifier: enables
  review:
    summary: Structural study of the SIAH1-SIP interaction within the beta-catenin destruction E3 complex. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real, structurally characterized interaction (SIP/CACYBP) central to the beta-catenin destruction complex, but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: SIP engages Siah1 by means of two elements, both of which are required for mediating beta-catenin destruction in cells
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:16085652
  qualifier: enables
  review:
    summary: Structural evidence that SIAH1 coordinates zinc through its RING and SIAH-type zinc fingers. Required for the fold and catalysis.
    action: ACCEPT
    reason: Structurally demonstrated zinc binding; essential for the RING/SIAH-domain fold and catalytic activity.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: Siah1 is the central component of a multiprotein E3 ubiquitin ligase complex
- term:
    id: GO:0030877
    label: beta-catenin destruction complex
  evidence_type: IDA
  original_reference_id: PMID:16085652
  qualifier: part_of
  review:
    summary: Structural evidence that SIAH1 is the central component of the multiprotein E3 complex (with SIP/CACYBP, SKP1, Ebi/TBL1X) that targets beta-catenin for destruction. Core cellular component for the Wnt-related role.
    action: ACCEPT
    reason: Core cellular component; SIAH1 is the central RING subunit of the p53-inducible beta-catenin destruction complex.
    supported_by:
    - reference_id: PMID:16085652
      supporting_text: Siah1 is the central component of a multiprotein E3 ubiquitin ligase complex that targets beta-catenin for destruction in response to p53 activation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11389840
  qualifier: enables
  review:
    summary: Interaction with the C-terminus of APC in the beta-catenin degradation pathway. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real, functionally important interaction (APC) but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:11389840
      supporting_text: Siah-1 interacts with the carboxyl terminus of APC and promotes degradation of beta-catenin in mammalian cells
- term:
    id: GO:0030163
    label: protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:11389840
  qualifier: involved_in
  review:
    summary: Direct evidence that SIAH1 promotes beta-catenin degradation (GSK3beta/beta-TrCP-independent, p53-inducible). Core biological process (generic level).
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific proteasome-mediated ubiquitin-dependent catabolic process annotation better captures the role.
    supported_by:
    - reference_id: PMID:11389840
      supporting_text: APC and Siah-1 mediate a novel beta-catenin degradation pathway linking p53 activation to cell cycle control
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:9334332
  qualifier: located_in
  review:
    summary: Author-statement (immunofluorescence) evidence that SIAH proteins localize predominantly in the cytoplasm. Core localization.
    action: ACCEPT
    reason: Core localization with direct support; SIAH1 is predominantly cytoplasmic.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the Sina/Siah proteins localized predominantly in the cytoplasm
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: TAS
  original_reference_id: PMID:9403064
  qualifier: involved_in
  review:
    summary: Author-statement assignment of involvement in apoptosis from the original characterization of human seven-in-absentia homologs (p53-inducible apoptosis/tumor suppression).
    action: KEEP_AS_NON_CORE
    reason: SIAH1 genuinely participates in apoptosis, but this is a downstream/pleiotropic process of its ligase activity rather than its core molecular function.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: TAS
  original_reference_id: PMID:9334332
  qualifier: involved_in
  review:
    summary: Author-statement assignment of involvement in nervous system development, via SIAH1 regulation of the netrin receptor DCC.
    action: KEEP_AS_NON_CORE
    reason: SIAH1 genuinely contributes to nervous-system development (DCC regulation), but this is a downstream developmental process of its ligase activity, not the core function.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: the DCC cytoplasmic domain binds to proteins encoded by mammalian homologs of the Drosophila seven in absentia (sina) gene
- term:
    id: GO:0007411
    label: axon guidance
  evidence_type: TAS
  original_reference_id: PMID:9334332
  qualifier: involved_in
  review:
    summary: Author-statement assignment of involvement in axon guidance, via SIAH1 regulation of the netrin/DCC axon-guidance receptor.
    action: KEEP_AS_NON_CORE
    reason: SIAH1 genuinely contributes to axon guidance (DCC regulation), but this is a downstream developmental process of its ligase activity, not the core function.
    supported_by:
    - reference_id: PMID:9334332
      supporting_text: DCC (deleted in colorectal cancer) is postulated to function as transmembrane receptor for the axon and cell guidance factor netrin-1
- term:
    id: GO:0009653
    label: anatomical structure morphogenesis
  evidence_type: TAS
  original_reference_id: PMID:9403064
  qualifier: involved_in
  review:
    summary: Author-statement assignment of involvement in morphogenesis from the original characterization of human seven-in-absentia homologs.
    action: KEEP_AS_NON_CORE
    reason: A generic developmental process downstream of SIAH1's pleiotropic substrate-degradation roles, not its core function.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:11863358
  qualifier: enables
  review:
    summary: Zinc ion binding annotation. The cited reference (PMID:11863358) is an APOBEC C-to-U RNA-editing study on chromosome 22 with no mention of SIAH1 in the cached entry, so the citation appears to use a wrong identifier; however SIAH1 zinc binding itself is correct and independently supported.
    action: ACCEPT
    reason: SIAH1 zinc ion binding is structurally established (RING + SIAH-type zinc fingers; PMID:16085652), so the annotation is biologically correct and accepted. The cited PMID:11863358 is flagged as a probable wrong-identifier citation in the reference review.
    supported_by:
    - reference_id: file:human/SIAH1/SIAH1-uniprot.txt
      supporting_text: ZN_FING
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  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:0000041
  title: Gene Ontology annotation based on UniPathway 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:9334332
  title: Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome
    pathway.
  findings:
  - statement: SIAH proteins bind the DCC cytoplasmic domain, interact with ubiquitin-conjugating enzymes, localize predominantly to the cytoplasm, and regulate DCC via proteasome-dependent degradation; an N-terminal Ubc-binding-deficient mutant binds but cannot degrade DCC.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; foundational study establishing SIAH1 as a cytoplasmic RING E3 that binds E2 enzymes and degrades DCC via the proteasome.
- id: PMID:9403064
  title: Characterization of human homologs of the Drosophila seven in absentia (sina)
    gene.
  findings:
  - statement: Original characterization of human SIAH genes, linking them to p53-inducible apoptosis, tumor suppression and developmental processes.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the apoptosis and anatomical-structure-morphogenesis TAS annotations.
- id: PMID:11389840
  title: Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the
    adenomatous polyposis coli protein.
  findings:
  - statement: Siah-1 interacts with the APC C-terminus and promotes GSK3beta/beta-TrCP-independent, p53-inducible degradation of beta-catenin.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only in cache; establishes the SIAH1 beta-catenin degradation pathway.
- id: PMID:11483518
  title: Regulation of BOB.1/OBF.1 stability by SIAH.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes BOB.1/OBF.1 (POU2AF1) as a SIAH substrate; source of a bare protein binding annotation.
- id: PMID:11863358
  title: An anthropoid-specific locus of orphan C to U RNA-editing enzymes on chromosome
    22.
  findings:
  - statement: The cached entry is about APOBEC C-to-U RNA-editing enzymes on chromosome 22 and does not mention SIAH1; it is cited for a SIAH1 zinc ion binding annotation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: NONE
    correctness: WRONG_IDENTIFIER
    review_notes: The cited paper (APOBEC RNA-editing enzymes) has no relation to SIAH1 - the cached abstract contains zero mention of SIAH1/seven-in-absentia. The zinc ion binding annotation citing this PMID appears to use a wrong identifier; SIAH1 zinc binding is independently supported by PMID:16085652.
- id: PMID:16085652
  title: Structural analysis of Siah1-Siah-interacting protein interactions and insights
    into the assembly of an E3 ligase multiprotein complex.
  findings:
  - statement: Siah1 is the central component of a multiprotein E3 ligase complex (with SIP/CACYBP, SKP1, Ebi) that targets beta-catenin for destruction in response to p53; SIP binds Siah1 via a consensus PXAXVXP motif and provides the scaffold positioning substrate and E2.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; source of zinc ion binding (IDA) and beta-catenin destruction complex annotations.
- id: PMID:16230351
  title: Siah1 interacts with the scaffold protein POSH to promote JNK activation
    and apoptosis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes the SIAH1-POSH-JNK apoptosis link; source of a bare protein binding annotation.
- id: PMID:19224863
  title: Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates alpha-synuclein
    monoubiquitylation and inclusion formation.
  findings:
  - statement: SIAH is a ubiquitin-protein isopeptide ligase that ubiquitylates alpha-synuclein and synphilin-1 and is present in Lewy bodies; synphilin-1A inhibits SIAH activity and self-ubiquitination, modulating alpha-synuclein monoubiquitination and inclusion formation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; experimental (EXP) support for SIAH1 ligase activity on alpha-synuclein/synphilin-1.
- id: PMID:19549727
  title: Analysis of the human E2 ubiquitin conjugating enzyme protein interaction
    network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput E2 interaction network; source of a bare protein binding annotation, consistent with SIAH1 binding E2 enzymes.
- id: PMID:21078624
  title: Comparison of an expanded ataxia interactome with patient medical records
    reveals a relationship between macular degeneration and ataxia.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:21185211
  title: ARTS and Siah collaborate in a pathway for XIAP degradation.
  findings:
  - statement: ARTS (SEPT4) bridges Siah-1 to XIAP, inducing XIAP ubiquitination and degradation; cells lacking Siah or ARTS have higher XIAP, linking SIAH1 to pro-apoptotic XIAP turnover.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the SIAH1-ARTS-XIAP apoptosis pathway.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:21878328
  title: E3 ubiquitin ligase Siah-1 facilitates poly-ubiquitylation and proteasomal
    degradation of the hepatitis B viral X protein.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes HBx as a SIAH1 substrate; source of a bare protein binding annotation.
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput liver interactome; source of bare protein binding and identical protein binding (self-association) annotations.
- id: PMID:22493164
  title: Systematic analysis of dimeric E3-RING interactions reveals increased combinatorial
    complexity in human ubiquitination networks.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the identical protein binding (SIAH1 self-association/dimerization) annotation; consistent with SIAH1 functioning as a homodimer.
- id: PMID:23001567
  title: Polycystin-1 regulates the stability and ubiquitination of transcription
    factor Jade-1.
  findings:
  - statement: Jade-1 ubiquitination is mediated by Siah-1; polycystin-1 (PC1) stabilizes Jade-1 while PC1 C-terminal fragments promote Siah-1-dependent Jade-1 ubiquitination and degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; IDA support for SIAH1 ligase activity and ubiquitin-dependent catabolism of Jade-1.
- id: PMID:23840749
  title: 'MOR is not enough: identification of novel mu-opioid receptor interacting
    proteins using traditional and modified membrane yeast two-hybrid screens.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interaction screen; source of a bare protein binding annotation.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of bare protein binding and identical protein binding annotations.
- id: PMID:28546513
  title: The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating
    Wnt-induced Axin degradation.
  findings:
  - statement: SIAH1/2 are the E3 ligases mediating Wnt-induced ubiquitination and proteasomal degradation of AXIN1 (via a VxP motif), counteracted by GSK3 binding; SIAH1 knockout blocks Wnt-induced Axin ubiquitination and attenuates beta-catenin stabilization, a feed-forward mechanism sustaining Wnt signaling.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the SIAH1-AXIN1 axis and the positive (feed-forward) Wnt-signaling role.
- id: PMID:32430360
  title: De novo variants in SIAH1, encoding an E3 ubiquitin ligase, are associated
    with developmental delay, hypotonia and dysmorphic features.
  findings:
  - statement: De novo SIAH1 variants cause a neurodevelopmental disorder and perturb Wnt signaling, supporting SIAH1 function in canonical Wnt signaling and development.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Disease-variant evidence; source of a canonical Wnt signaling annotation.
- id: PMID:33591310
  title: DAZAP2 acts as specifier of the p53 response to DNA damage.
  findings:
  - statement: DAZAP2 stimulates HIPK2 polyubiquitination and degradation through interplay with the ubiquitin ligase SIAH1 in unstressed cells; DNA damage triggers HIPK2-mediated DAZAP2 phosphorylation that terminates this degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; IDA support for SIAH1-mediated proteasomal degradation of HIPK2 in the DNA-damage/p53 response.
- id: Reactome:R-HSA-374665
  title: DCC interaction with SIAH1
  findings: []
- id: Reactome:R-HSA-5658092
  title: SIAH1, SIAH2 bind SNCAIP
  findings: []
- id: Reactome:R-HSA-5658496
  title: SIAH1:UBE2L6:Ubiquitin binds SNCA
  findings: []
- id: Reactome:R-HSA-5660753
  title: SIAH1:UBE2L6:Ubiquitin ubiquitinates SNCA
  findings: []
- id: Reactome:R-HSA-5660757
  title: Ub-SNCA dissociates from the conjugating enzyme
  findings: []
- id: Reactome:R-HSA-5667107
  title: SIAH1, SIAH2 ubiquitinate SNCAIP
  findings: []
- id: Reactome:R-HSA-977225
  title: Amyloid fiber formation
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
core_functions:
- description: Functions as a catalytic RING-type E3 ubiquitin-protein ligase that recruits a ubiquitin-charged E2 conjugating enzyme via its N-terminal RING domain and transfers ubiquitin to substrate lysines, directing substrates for proteasomal degradation; functions as a homodimer and recognizes substrate degrons (often a PxAxVxP/VxP motif) through its C-terminal SIAH-type substrate-binding domain.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:9334332
    supporting_text: the Sina/Siah proteins interacted with ubiquitin-conjugating enzymes (Ubcs)
  - reference_id: PMID:19224863
    supporting_text: the ubiquitin-protein isopeptide ligase SIAH
  directly_involved_in:
  - id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
- description: Acts as the central RING subunit of a p53-inducible multiprotein E3 ligase complex (with SIP/CACYBP, SKP1, Ebi/TBL1X and APC) that targets beta-catenin for GSK3beta/beta-TrCP-independent destruction, and separately ubiquitinates AXIN1 in a Wnt-induced feed-forward loop; together these make SIAH1 a regulator of canonical Wnt/beta-catenin signaling.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:16085652
    supporting_text: Siah1 is the central component of a multiprotein E3 ubiquitin ligase complex that targets beta-catenin for destruction in response to p53 activation
  - reference_id: PMID:28546513
    supporting_text: SIAH proteins promote the ubiquitination and proteasomal degradation of Axin
  directly_involved_in:
  - id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
- description: Ubiquitinates substrates that control apoptosis, the DNA-damage/p53 response and Parkinson-disease biology, including XIAP (via the ARTS adaptor, promoting intrinsic apoptosis), the kinase HIPK2 (DAZAP2-assisted), the netrin receptor DCC (nervous-system development/axon guidance), and alpha-synuclein/synphilin-1 (linking SIAH1 to Lewy-body inclusion formation).
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:21185211
    supporting_text: ARTS serves as an adaptor to bridge Siah-1 to XIAP, targeting it for destruction
  - reference_id: PMID:33591310
    supporting_text: DAZAP2 stimulates HIPK2 polyubiquitination and degradation through interplay with the ubiquitin ligase SIAH1
  directly_involved_in:
  - id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: How does SIAH1 select among its many substrates (DCC, beta-catenin, AXIN1, XIAP, HIPK2, SNCA/SNCAIP, EGLN2/3) - is selection governed by adaptor proteins (SIP/CACYBP, ARTS, DAZAP2), subcellular pool, dimerization state, or stimulus (p53, hypoxia, DNA damage)?
- question: Given that SIAH1 both degrades beta-catenin (negative) and degrades AXIN1 to sustain Wnt signaling (positive), what determines the net direction of its effect on canonical Wnt signaling in a given cell context?
suggested_experiments:
- description: Perform quantitative ubiquitinome/proteome profiling in SIAH1-knockout versus wild-type cells under basal, p53-activated, hypoxic and DNA-damage conditions to define the stimulus-dependent endogenous SIAH1 substrate repertoire and distinguish core degradative substrates from context-specific ones.
- description: Reconstitute SIAH1-mediated ubiquitination in vitro with purified SIAH1 (wild-type vs RING and substrate-binding-domain mutants), E1, E2 panels and individual substrates/adaptors (SIP, ARTS, DAZAP2) to map how adaptors and dimerization control substrate choice and chain assembly.