Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of proteasome-mediated ubiquitin-dependent protein catabolism, the core biological process of SIAH1, which targets numerous substrates for proteasomal degradation. Reason: Core biological process; SIAH1 ubiquitinates substrates (DCC, beta-catenin, XIAP, HIPK2, AXIN1) for proteasomal degradation, demonstrated by proteasome-inhibitor-sensitive degradation assays. Supporting Evidence: PMID:9334332 Proteasome inhibitors blocked the effects of Sina/Siah on DCC
GO:0061630 ubiquitin protein ligase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of ubiquitin protein ligase activity, the core molecular function of SIAH1 as a genuine RING-type E3 ligase. Reason: Core molecular function; SIAH1 is a catalytic RING E3 ligase, corroborated by experimental EXP/IDA evidence. Supporting Evidence: PMID:19224863 the ubiquitin-protein isopeptide ligase SIAH
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that SIAH1 is active in the cytoplasm, its dominant subcellular compartment and site of action on most substrates. Reason: Core localization; SIAH1 is predominantly cytoplasmic, where it associates with and degrades substrates such as DCC. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0031624 ubiquitin conjugating enzyme binding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of E2 (ubiquitin-conjugating enzyme) binding, a defining feature of the SIAH1 RING domain and essential to its catalytic mechanism. Reason: Core molecular function; SIAH1 binds E2 enzymes (Ubcs) through its N-terminal RING region, and a Ubc-binding-deficient mutant cannot degrade substrate. Supporting Evidence: PMID:9334332 the Sina/Siah proteins interacted with ubiquitin-conjugating enzymes (Ubcs)
GO:0005634 nucleus	IEA GO_REF:0000120	KEEP AS NON CORE	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). Reason: Real secondary localization (nuclear substrates such as HIPK2), but the dominant active compartment is cytoplasmic. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of cytoplasmic localization, the dominant compartment of SIAH1. Reason: Core localization; redundant with the IBA cytoplasm and TAS cytoplasm annotations. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0006511 ubiquitin-dependent protein catabolic process	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic assignment of ubiquitin-dependent protein catabolism, a parent of the specific proteasome-mediated catabolic process SIAH1 mediates. Reason: Correct but more generic; the specific proteasome-mediated ubiquitin-dependent catabolic process annotation better captures the role. Supporting Evidence: PMID:9334332 the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway
GO:0008270 zinc ion binding	IEA GO_REF:0000002	ACCEPT	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. Reason: Structurally required; the RING and SIAH-type zinc fingers coordinate zinc, essential for the fold and catalysis. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt ZN_FING
GO:0060070 canonical Wnt signaling pathway	IEA GO_REF:0000117	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:28546513 SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/β-catenin signaling
GO:0061630 ubiquitin protein ligase activity	IEA GO_REF:0000003	ACCEPT	Summary: Enzyme Commission-based electronic assignment of ubiquitin protein ligase activity (EC 2.3.2.27), the core catalytic molecular function. Reason: Core molecular function; redundant with the IBA/EXP/IDA ligase activity annotations. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt EC=2.3.2.27
GO:1990000 amyloid fibril formation	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:19224863 SIAH also increases the formation of synphilin-1A inclusions
GO:2001233 regulation of apoptotic signaling pathway	IEA GO_REF:0000117	KEEP AS NON CORE	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. Reason: SIAH1 genuinely regulates apoptosis (XIAP degradation, POSH/JNK), but this is a downstream biological outcome rather than its core function. Supporting Evidence: PMID:21185211 ARTS interacts with the E3 ligase Siah-1 (seven in absentia homolog 1) to induce ubiquitination and degradation of XIAP
GO:0005515 protein binding	IPI PMID:11483518 Regulation of BOB.1/OBF.1 stability by SIAH.	KEEP AS NON CORE	Summary: Interaction with BOB.1/OBF.1 (POU2AF1), whose stability SIAH regulates. Bare protein binding is uninformative. Reason: Records a real interaction (BOB.1/OBF.1) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005515 protein binding	IPI PMID:16230351 Siah1 interacts with the scaffold protein POSH to promote JN...	KEEP AS NON CORE	Summary: Interaction with the scaffold protein POSH (promotes JNK activation and apoptosis). Bare protein binding is uninformative. Reason: Records a real interaction (POSH) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005515 protein binding	IPI PMID:19549727 Analysis of the human E2 ubiquitin conjugating enzyme protei...	KEEP AS NON CORE	Summary: Interaction from the human E2 ubiquitin-conjugating enzyme network (E2 binding). Bare protein binding is uninformative. 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. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005515 protein binding	IPI PMID:21078624 Comparison of an expanded ataxia interactome with patient me...	KEEP AS NON CORE	Summary: Interaction from an expanded ataxia interactome. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005515 protein binding	IPI PMID:21185211 ARTS and Siah collaborate in a pathway for XIAP degradation.	KEEP AS NON CORE	Summary: Interaction with XIAP/ARTS in the XIAP-degradation pathway. Bare protein binding is uninformative. Reason: Records real, functionally important interactions (ARTS/XIAP) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: PMID:21185211 ARTS interacts with the E3 ligase Siah-1 (seven in absentia homolog 1) to induce ubiquitination and degradation of XIAP
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	KEEP AS NON CORE	Summary: High-throughput interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005515 protein binding	IPI PMID:21878328 E3 ubiquitin ligase Siah-1 facilitates poly-ubiquitylation a...	KEEP AS NON CORE	Summary: Interaction with the hepatitis B viral X protein (HBx), a SIAH1 substrate. Bare protein binding is uninformative. Reason: Records a real substrate interaction (HBx) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	KEEP AS NON CORE	Summary: Human liver protein interaction network interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005515 protein binding	IPI PMID:23840749 MOR is not enough: identification of novel mu-opioid recepto...	KEEP AS NON CORE	Summary: Interaction from a mu-opioid receptor interacting-protein screen. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Proteome-scale interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0042802 identical protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	KEEP AS NON CORE	Summary: Self-association evidence; SIAH1 functions as a homodimer (and can heterodimerize with SIAH2). A real, informative homotypic interaction. Reason: SIAH1 genuinely homodimerizes, which is required for its function, but this is a structural property supporting rather than defining the core ligase activity. Supporting Evidence: PMID:22493164 dimeric E3-RING interactions
GO:0042802 identical protein binding	IPI PMID:22493164 Systematic analysis of dimeric E3-RING interactions reveals ...	KEEP AS NON CORE	Summary: Systematic dimeric E3-RING interaction analysis; SIAH1 self-associates (homodimer). A real homotypic interaction. Reason: SIAH1 self-associates (homodimer); supports its function but is not the core catalytic role. Supporting Evidence: PMID:22493164 dimeric E3-RING interactions
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Proteome-scale interactome self-interaction (SIAH1 homodimerization). Reason: SIAH1 self-associates (homodimer); supports its function but is not the core catalytic role. Supporting Evidence: PMID:22493164 dimeric E3-RING interactions
GO:0004842 ubiquitin-protein transferase activity	IEA GO_REF:0000107	ACCEPT	Summary: Ortholog-transferred (Ensembl Compara) ubiquitin-protein transferase activity, the core catalytic molecular function of SIAH1. Reason: Core molecular function; synonymous with ubiquitin protein ligase activity for this catalytic RING E3. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt EC=2.3.2.27
GO:0005769 early endosome	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara) early endosome localization. Not strongly supported by primary human SIAH1 literature, which emphasizes cytoplasmic and nuclear pools. 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. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0005829 cytosol	IEA GO_REF:0000107	ACCEPT	Summary: Ortholog-transferred (Ensembl Compara) cytosolic localization, consistent with the dominant cytoplasmic compartment of SIAH1. Reason: Core localization; consistent with the cytoplasmic/cytosolic site of action. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0031648 protein destabilization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara) protein destabilization, a consequence of SIAH1-mediated ubiquitination and degradation of its substrates. Reason: Correct as a consequence of SIAH1's degradative activity, but the catabolic-process and ligase-activity annotations capture the mechanism more directly. Supporting Evidence: PMID:9334332 the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway
GO:0051402 neuron apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-transferred (Ensembl Compara) involvement in neuron apoptosis, consistent with SIAH1's pro-apoptotic role and Parkinson-disease-related substrates. Reason: A downstream, context-specific (neuronal) process of SIAH1's apoptosis-promoting activity, not its core function. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: UniPathway-derived general protein ubiquitination process, the core catalytic process of SIAH1 (here at a generic level). Reason: Correct but generic; the specific proteasome-mediated catabolic process annotation better captures the role. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt PATHWAY: Protein modification; protein ubiquitination.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Immunofluorescence (Human Protein Atlas) evidence of nucleoplasmic localization; the real but secondary nuclear pool of SIAH1. Reason: Experimentally supported nuclear pool (consistent with nuclear substrates such as HIPK2) but secondary to the dominant cytoplasmic compartment. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0061630 ubiquitin protein ligase activity	EXP PMID:19224863 Synphilin-1A inhibits seven in absentia homolog (SIAH) and m...	ACCEPT	Summary: Experimental evidence that SIAH is a ubiquitin-protein (isopeptide) ligase that ubiquitylates alpha-synuclein and synphilin-1. Core molecular function. Reason: Core molecular function with direct experimental support; SIAH1 is a catalytic RING E3 ligase. Supporting Evidence: PMID:19224863 the ubiquitin-protein isopeptide ligase SIAH
GO:0004842 ubiquitin-protein transferase activity	TAS Reactome:R-HSA-5660753	ACCEPT	Summary: Reactome curation (SIAH1:UBE2L6:Ubiquitin ubiquitinates SNCA) of ubiquitin-protein transferase activity, the core catalytic molecular function. Reason: Core molecular function; SIAH1 transfers ubiquitin (with E2 UBE2L6) to its substrate SNCA. Synonymous with ubiquitin protein ligase activity. Supporting Evidence: PMID:19224863 ubiquitin-ligase that ubiquitylates alpha-synuclein and synphilin-1
GO:0004842 ubiquitin-protein transferase activity	TAS Reactome:R-HSA-5667107	ACCEPT	Summary: Reactome curation (SIAH1, SIAH2 ubiquitinate SNCAIP) of ubiquitin-protein transferase activity, the core catalytic molecular function. Reason: Core molecular function; SIAH1 transfers ubiquitin to synphilin-1 (SNCAIP). Synonymous with ubiquitin protein ligase activity. Supporting Evidence: PMID:19224863 ubiquitin-ligase that ubiquitylates alpha-synuclein and synphilin-1
GO:1990000 amyloid fibril formation	TAS Reactome:R-HSA-977225	MARK AS OVER ANNOTATED	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. 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). Supporting Evidence: PMID:19224863 SIAH also increases the formation of synphilin-1A inclusions
GO:0005515 protein binding	IPI PMID:33591310 DAZAP2 acts as specifier of the p53 response to DNA damage.	KEEP AS NON CORE	Summary: Interaction with HIPK2/DAZAP2 in the DNA-damage/p53 response. Bare protein binding is uninformative. Reason: Records real, functionally important interactions (HIPK2/DAZAP2) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: PMID:33591310 DAZAP2 stimulates HIPK2 polyubiquitination and degradation through interplay with the ubiquitin ligase SIAH1
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IDA PMID:33591310 DAZAP2 acts as specifier of the p53 response to DNA damage.	ACCEPT	Summary: Direct evidence that SIAH1 drives polyubiquitination and degradation of HIPK2 (DAZAP2-assisted) in the DNA-damage/p53 response. Core biological process. Reason: Core biological process directly demonstrated; SIAH1 targets HIPK2 for proteasomal degradation. Supporting Evidence: PMID:33591310 DAZAP2 stimulates HIPK2 polyubiquitination and degradation through interplay with the ubiquitin ligase SIAH1
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IMP PMID:28546513 The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signalin...	ACCEPT	Summary: Mutant-phenotype evidence that SIAH1 promotes ubiquitination and proteasomal degradation of AXIN1 (SIAH1 knockout blocks Wnt-induced Axin ubiquitination). Core biological process. Reason: Core biological process; SIAH1 targets AXIN1 for proteasomal degradation, demonstrated by knockout. Supporting Evidence: PMID:28546513 SIAH proteins promote the ubiquitination and proteasomal degradation of Axin
GO:0060070 canonical Wnt signaling pathway	IMP PMID:28546513 The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signalin...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:28546513 Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced β-catenin stabilization
GO:0060070 canonical Wnt signaling pathway	IMP PMID:32430360 De novo variants in SIAH1, encoding an E3 ubiquitin ligase, ...	KEEP AS NON CORE	Summary: De novo SIAH1 variants associated with developmental delay also affect Wnt signaling; mutant-phenotype evidence linking SIAH1 to the canonical Wnt pathway. Reason: Supports SIAH1 involvement in canonical Wnt signaling (disease-variant evidence), but this is a downstream pathway role rather than the core function. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0061630 ubiquitin protein ligase activity	IMP PMID:28546513 The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signalin...	ACCEPT	Summary: Mutant-phenotype evidence (SIAH1 knockout abolishes Wnt-induced Axin ubiquitination) supporting SIAH1 ubiquitin protein ligase activity. Core molecular function. Reason: Core molecular function; SIAH1 ligase activity is required for AXIN1 ubiquitination. Supporting Evidence: PMID:28546513 Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination
GO:0005515 protein binding	IPI PMID:28546513 The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signalin...	KEEP AS NON CORE	Summary: Interaction with AXIN1 (a SIAH1 substrate) via a VxP motif. Bare protein binding is uninformative. Reason: Records a real substrate interaction (AXIN1) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: PMID:28546513 SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin
GO:0061630 ubiquitin protein ligase activity	IDA PMID:23001567 Polycystin-1 regulates the stability and ubiquitination of t...	ACCEPT	Summary: Direct evidence that SIAH1 (Siah-1) mediates ubiquitination of the transcription factor Jade-1. Core molecular function. Reason: Core molecular function directly demonstrated; SIAH1 ubiquitinates Jade-1. Supporting Evidence: PMID:23001567 Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1
GO:2001244 positive regulation of intrinsic apoptotic signaling pathway	IMP PMID:21185211 ARTS and Siah collaborate in a pathway for XIAP degradation.	KEEP AS NON CORE	Summary: SIAH1 (with the ARTS adaptor) promotes XIAP degradation, lowering the apoptotic threshold; cells lacking Siah contain higher XIAP. A pro-apoptotic downstream role. 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. Supporting Evidence: PMID:21185211 Cells lacking either Siah or ARTS contain higher steady-state levels of XIAP
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:23001567 Polycystin-1 regulates the stability and ubiquitination of t...	KEEP AS NON CORE	Summary: Direct evidence that SIAH1 mediates ubiquitin-dependent catabolism of Jade-1. Core biological process (generic level). Reason: Correct but the more specific proteasome-mediated catabolic process annotation better captures the role; retained as non-core given the generic parent term. Supporting Evidence: PMID:23001567 Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1
GO:0005829 cytosol	TAS Reactome:R-HSA-374665	ACCEPT	Summary: Reactome curation of cytosolic localization (DCC interaction with SIAH1). Consistent with the core cytoplasmic site of action. Reason: Correct core cytosolic localization where SIAH1 binds and degrades DCC. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-5658092	ACCEPT	Summary: Reactome curation of cytosolic localization (SIAH1, SIAH2 bind SNCAIP). Consistent with the core cytoplasmic site of action. Reason: Correct core cytosolic localization where SIAH1 acts on synphilin-1. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-5658496	ACCEPT	Summary: Reactome curation of cytosolic localization (SIAH1:UBE2L6:Ubiquitin binds SNCA). Consistent with the core cytoplasmic site of action. Reason: Correct core cytosolic localization where SIAH1 acts on alpha-synuclein. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-5660753	ACCEPT	Summary: Reactome curation of cytosolic localization (SIAH1:UBE2L6:Ubiquitin ubiquitinates SNCA). Consistent with the core cytoplasmic site of action. Reason: Correct core cytosolic localization. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-5660757	ACCEPT	Summary: Reactome curation of cytosolic localization (Ub-SNCA dissociates from the conjugating enzyme). Consistent with the core cytoplasmic site of action. Reason: Correct core cytosolic localization. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-5667107	ACCEPT	Summary: Reactome curation of cytosolic localization (SIAH1, SIAH2 ubiquitinate SNCAIP). Consistent with the core cytoplasmic site of action. Reason: Correct core cytosolic localization. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-983140	ACCEPT	Summary: Reactome curation of cytosolic localization (generic transfer of Ub from E2 to substrate). Consistent with the core cytoplasmic site of action. Reason: Correct cytosolic compartment for the ubiquitination reaction; from generic ubiquitination-pathway context. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-983147	ACCEPT	Summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Consistent with the core cytoplasmic site of action. Reason: Correct cytosolic compartment; from generic ubiquitination-pathway context. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-983156	ACCEPT	Summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Consistent with the core cytoplasmic site of action. Reason: Correct cytosolic compartment; from generic ubiquitination-pathway context. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0005829 cytosol	TAS Reactome:R-HSA-983157	ACCEPT	Summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub complex). Consistent with the core cytoplasmic site of action. Reason: Correct cytosolic compartment; from generic ubiquitination-pathway context. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0004842 ubiquitin-protein transferase activity	IMP PMID:21185211 ARTS and Siah collaborate in a pathway for XIAP degradation.	ACCEPT	Summary: Mutant-phenotype evidence supporting SIAH1 ubiquitin-protein transferase activity in the ARTS-mediated XIAP degradation pathway. Core molecular function. Reason: Core molecular function; SIAH1 ligase activity drives XIAP ubiquitination/degradation. Supporting Evidence: PMID:21185211 ARTS interacts with the E3 ligase Siah-1 (seven in absentia homolog 1) to induce ubiquitination and degradation of XIAP
GO:0043065 positive regulation of apoptotic process	IDA PMID:21185211 ARTS and Siah collaborate in a pathway for XIAP degradation.	KEEP AS NON CORE	Summary: SIAH1 promotes apoptosis by degrading XIAP (via ARTS). A downstream pro-apoptotic role of its ligase activity. Reason: SIAH1 genuinely promotes apoptosis (XIAP degradation), but this is a downstream biological process rather than the core molecular function. Supporting Evidence: PMID:21185211 ARTS serves as an adaptor to bridge Siah-1 to XIAP, targeting it for destruction
GO:0005634 nucleus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity-based assignment of nuclear localization; the real but secondary nuclear pool of SIAH1. 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. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0051402 neuron apoptotic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity-based assignment of involvement in neuron apoptosis, consistent with SIAH1's pro-apoptotic role and Parkinson-related substrates. Reason: A downstream, neuronal-context process of SIAH1's apoptosis-promoting activity, not its core function. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0004842 ubiquitin-protein transferase activity	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity-based assignment of ubiquitin-protein transferase activity, the core catalytic molecular function of SIAH1. Reason: Core molecular function; redundant with the experimental ligase/transferase annotations. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt EC=2.3.2.27
GO:0006511 ubiquitin-dependent protein catabolic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity-based assignment of ubiquitin-dependent protein catabolism, a parent of the specific proteasome-mediated catabolic process SIAH1 mediates. Reason: Correct but generic; the specific proteasome-mediated catabolic process annotation better captures the role. Supporting Evidence: PMID:9334332 the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway
GO:0008270 zinc ion binding	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity-based assignment of zinc ion binding; SIAH1 has a RING-type zinc finger and SIAH-type zinc fingers. Reason: Structurally required; the RING and SIAH-type zinc fingers coordinate zinc. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt ZN_FING
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity-based assignment of proteasome-mediated ubiquitin-dependent catabolism, the core biological process of SIAH1. Reason: Core biological process; redundant with the IBA/IDA/IMP catabolic-process annotations. Supporting Evidence: PMID:9334332 Proteasome inhibitors blocked the effects of Sina/Siah on DCC
GO:0005515 protein binding	IPI PMID:16085652 Structural analysis of Siah1-Siah-interacting protein intera...	KEEP AS NON CORE	Summary: Structural study of the SIAH1-SIP interaction within the beta-catenin destruction E3 complex. Bare protein binding is uninformative. 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. Supporting Evidence: PMID:16085652 SIP engages Siah1 by means of two elements, both of which are required for mediating beta-catenin destruction in cells
GO:0008270 zinc ion binding	IDA PMID:16085652 Structural analysis of Siah1-Siah-interacting protein intera...	ACCEPT	Summary: Structural evidence that SIAH1 coordinates zinc through its RING and SIAH-type zinc fingers. Required for the fold and catalysis. Reason: Structurally demonstrated zinc binding; essential for the RING/SIAH-domain fold and catalytic activity. Supporting Evidence: PMID:16085652 Siah1 is the central component of a multiprotein E3 ubiquitin ligase complex
GO:0030877 beta-catenin destruction complex	IDA PMID:16085652 Structural analysis of Siah1-Siah-interacting protein intera...	ACCEPT	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. Reason: Core cellular component; SIAH1 is the central RING subunit of the p53-inducible beta-catenin destruction complex. Supporting Evidence: PMID:16085652 Siah1 is the central component of a multiprotein E3 ubiquitin ligase complex that targets beta-catenin for destruction in response to p53 activation
GO:0005515 protein binding	IPI PMID:11389840 Siah-1 mediates a novel beta-catenin degradation pathway lin...	KEEP AS NON CORE	Summary: Interaction with the C-terminus of APC in the beta-catenin degradation pathway. Bare protein binding is uninformative. Reason: Records a real, functionally important interaction (APC) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: PMID:11389840 Siah-1 interacts with the carboxyl terminus of APC and promotes degradation of beta-catenin in mammalian cells
GO:0030163 protein catabolic process	IDA PMID:11389840 Siah-1 mediates a novel beta-catenin degradation pathway lin...	KEEP AS NON CORE	Summary: Direct evidence that SIAH1 promotes beta-catenin degradation (GSK3beta/beta-TrCP-independent, p53-inducible). Core biological process (generic level). Reason: Correct but generic; the specific proteasome-mediated ubiquitin-dependent catabolic process annotation better captures the role. Supporting Evidence: PMID:11389840 APC and Siah-1 mediate a novel beta-catenin degradation pathway linking p53 activation to cell cycle control
GO:0005737 cytoplasm	TAS PMID:9334332 Mammalian homologs of seven in absentia regulate DCC via the...	ACCEPT	Summary: Author-statement (immunofluorescence) evidence that SIAH proteins localize predominantly in the cytoplasm. Core localization. Reason: Core localization with direct support; SIAH1 is predominantly cytoplasmic. Supporting Evidence: PMID:9334332 the Sina/Siah proteins localized predominantly in the cytoplasm
GO:0006915 apoptotic process	TAS PMID:9403064 Characterization of human homologs of the Drosophila seven i...	KEEP AS NON CORE	Summary: Author-statement assignment of involvement in apoptosis from the original characterization of human seven-in-absentia homologs (p53-inducible apoptosis/tumor suppression). Reason: SIAH1 genuinely participates in apoptosis, but this is a downstream/pleiotropic process of its ligase activity rather than its core molecular function. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0007399 nervous system development	TAS PMID:9334332 Mammalian homologs of seven in absentia regulate DCC via the...	KEEP AS NON CORE	Summary: Author-statement assignment of involvement in nervous system development, via SIAH1 regulation of the netrin receptor DCC. 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. Supporting Evidence: PMID:9334332 the DCC cytoplasmic domain binds to proteins encoded by mammalian homologs of the Drosophila seven in absentia (sina) gene
GO:0007411 axon guidance	TAS PMID:9334332 Mammalian homologs of seven in absentia regulate DCC via the...	KEEP AS NON CORE	Summary: Author-statement assignment of involvement in axon guidance, via SIAH1 regulation of the netrin/DCC axon-guidance receptor. Reason: SIAH1 genuinely contributes to axon guidance (DCC regulation), but this is a downstream developmental process of its ligase activity, not the core function. Supporting Evidence: PMID:9334332 DCC (deleted in colorectal cancer) is postulated to function as transmembrane receptor for the axon and cell guidance factor netrin-1
GO:0009653 anatomical structure morphogenesis	TAS PMID:9403064 Characterization of human homologs of the Drosophila seven i...	KEEP AS NON CORE	Summary: Author-statement assignment of involvement in morphogenesis from the original characterization of human seven-in-absentia homologs. Reason: A generic developmental process downstream of SIAH1's pleiotropic substrate-degradation roles, not its core function. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt SUBCELLULAR LOCATION
GO:0008270 zinc ion binding	IDA PMID:11863358 An anthropoid-specific locus of orphan C to U RNA-editing en...	ACCEPT	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. 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. Supporting Evidence: file:human/SIAH1/SIAH1-uniprot.txt ZN_FING

Core Functions

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:

ubiquitin protein ligase activity

Directly Involved In:

proteasome-mediated ubiquitin-dependent protein catabolic process

Cellular Locations:

cytoplasm cytosol

Supporting Evidence:

PMID:9334332
the Sina/Siah proteins interacted with ubiquitin-conjugating enzymes (Ubcs)
PMID:19224863
the ubiquitin-protein isopeptide ligase SIAH

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:

ubiquitin protein ligase activity

Directly Involved In:

proteasome-mediated ubiquitin-dependent protein catabolic process

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:16085652
Siah1 is the central component of a multiprotein E3 ubiquitin ligase complex that targets beta-catenin for destruction in response to p53 activation
PMID:28546513
SIAH proteins promote the ubiquitination and proteasomal degradation of Axin

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:

ubiquitin protein ligase activity

Directly Involved In:

proteasome-mediated ubiquitin-dependent protein catabolic process

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:21185211
ARTS serves as an adaptor to bridge Siah-1 to XIAP, targeting it for destruction
PMID:33591310
DAZAP2 stimulates HIPK2 polyubiquitination and degradation through interplay with the ubiquitin ligase SIAH1

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000003

Gene Ontology annotation based on Enzyme Commission mapping

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:9334332

Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway.

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.

PMID:9403064

Characterization of human homologs of the Drosophila seven in absentia (sina) gene.

Original characterization of human SIAH genes, linking them to p53-inducible apoptosis, tumor suppression and developmental processes.

PMID:11389840

Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein.

Siah-1 interacts with the APC C-terminus and promotes GSK3beta/beta-TrCP-independent, p53-inducible degradation of beta-catenin.

PMID:11483518

Regulation of BOB.1/OBF.1 stability by SIAH.

PMID:11863358

An anthropoid-specific locus of orphan C to U RNA-editing enzymes on chromosome 22.

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.

PMID:16085652

Structural analysis of Siah1-Siah-interacting protein interactions and insights into the assembly of an E3 ligase multiprotein complex.

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.

PMID:16230351

Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis.

PMID:19224863

Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates alpha-synuclein monoubiquitylation and inclusion formation.

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.

PMID:19549727

Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network.

PMID:21078624

Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia.

PMID:21185211

ARTS and Siah collaborate in a pathway for XIAP degradation.

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.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:21878328

E3 ubiquitin ligase Siah-1 facilitates poly-ubiquitylation and proteasomal degradation of the hepatitis B viral X protein.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:22493164

Systematic analysis of dimeric E3-RING interactions reveals increased combinatorial complexity in human ubiquitination networks.

PMID:23001567

Polycystin-1 regulates the stability and ubiquitination of transcription factor Jade-1.

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.

PMID:23840749

MOR is not enough: identification of novel mu-opioid receptor interacting proteins using traditional and modified membrane yeast two-hybrid screens.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:28546513

The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation.

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.

PMID:32430360

De novo variants in SIAH1, encoding an E3 ubiquitin ligase, are associated with developmental delay, hypotonia and dysmorphic features.

De novo SIAH1 variants cause a neurodevelopmental disorder and perturb Wnt signaling, supporting SIAH1 function in canonical Wnt signaling and development.

PMID:33591310

DAZAP2 acts as specifier of the p53 response to DNA damage.

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.

Reactome:R-HSA-374665

DCC interaction with SIAH1

Reactome:R-HSA-5658092

SIAH1, SIAH2 bind SNCAIP

Reactome:R-HSA-5658496

SIAH1:UBE2L6:Ubiquitin binds SNCA

Reactome:R-HSA-5660753

SIAH1:UBE2L6:Ubiquitin ubiquitinates SNCA

Reactome:R-HSA-5660757

Ub-SNCA dissociates from the conjugating enzyme

Reactome:R-HSA-5667107

SIAH1, SIAH2 ubiquitinate SNCAIP

Reactome:R-HSA-977225

Amyloid fiber formation

Reactome:R-HSA-983140

Transfer of Ub from E2 to substrate and release of E2

Reactome:R-HSA-983147

Release of E3 from polyubiquitinated substrate

Reactome:R-HSA-983156

Polyubiquitination of substrate

Reactome:R-HSA-983157

Interaction of E3 with substrate and E2-Ub complex

Suggested Experiments

Experiment: 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.

Experiment: 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.

📚 Additional Documentation

Notes

(SIAH1-notes.md)

SIAH1 (seven in absentia homolog 1) review notes

UniProt: Q8IUQ4 (SIAH1_HUMAN), 282 aa. EC 2.3.2.27. RING-type E3 ubiquitin ligase.

Domain architecture

RING-type zinc finger 41..76 (catalytic RING, recruits E2) [UniProt FT].
Two additional zinc fingers (93..153) within the SIAH-type substrate-binding domain (SBD).
Forms homodimers (and heterodimers with SIAH2). N-terminal RING; C-terminal SBD recognizes
substrate degrons (often a VxP/PxAxVxP motif).

Core molecular function

RING-type E3 ubiquitin-protein ligase / ubiquitin-protein transferase (EC 2.3.2.27).
Accepts ubiquitin from an E2 (thioester) and transfers directly to substrate.
[UniProt FUNCTION; EC 2.3.2.27 ECO:0000269|PubMed:19224863, PubMed:28546513]
Zinc ion binding (RING + Zn fingers structurally require Zn) [UniProt; PMID:16085652 structural; PMID:11863358].
Binds E2 ubiquitin-conjugating enzymes (UBE2D1, UBE2E2, UBE2I, UBE2L6) — "ubiquitin conjugating enzyme binding".
PMID:9334332

Substrates / processes (the heart of SIAH1 biology)

DCC (deleted in colorectal cancer) — first mammalian substrate; ubiquitin-proteasome degradation.
PMID:9334332
beta-catenin (CTNNB1) — Siah1 mediates a p53-inducible, GSK3beta/beta-TrCP-INDEPENDENT
beta-catenin degradation pathway via APC; part of a multiprotein E3 complex with SIP/CACYBP,
SKP1, Ebi (TBL1X). [PMID:11389840; PMID:16085652 "Siah1 is the central component of a multiprotein
E3 ubiquitin ligase complex that targets beta-catenin for destruction in response to p53 activation"]
-> beta-catenin destruction complex (GO:0030877) part_of PMID:16085652.
AXIN1 — Wnt-induced degradation; SIAH1/2 mediate Wnt-induced Axin degradation, a feed-forward
mechanism to sustain Wnt/beta-catenin signaling. NOTE: this is POSITIVE regulation of canonical Wnt
(degrading Axin promotes signaling), distinct from the beta-catenin-degrading (negative) role above.
PMID:28546513
De novo SIAH1 variants -> developmental delay; also affect Wnt. PMID:32430360
alpha-synuclein (SNCA) monoubiquitylation + synphilin-1 (SNCAIP) ubiquitination -> Lewy body /
inclusion formation; relevant to Parkinson disease. SIAH activity inhibited by synphilin-1A.
PMID:19224863. Also Reactome SIAH1 ubiquitinates SNCA/SNCAIP.
XIAP — ARTS (SEPT4) bridges SIAH1 to XIAP for degradation -> promotes apoptosis (intrinsic).
PMID:21185211
HIPK2 — constitutive degradation; DAZAP2 promotes SIAH1-mediated HIPK2 ubiquitination/degradation;
DNA-damage context (p53 response). PMID:33591310
Jade-1 (PHF17) — ubiquitination regulated by polycystin-1; "Jade-1 ubiquitination was mediated by
Siah-1". PMID:23001567
BOB.1/OBF.1 (POU2AF1) stability regulated by SIAH. PMID:11483518
HBx (hepatitis B X protein) poly-ubiquitylation/degradation. PMID:21878328
EGLN2/EGLN3 (PHD prolyl hydroxylases) — degraded by SIAH1/2 under UPR/hypoxia, stabilizing ATF4
(and indirectly HIF). [UniProt FUNCTION, By similarity] — hypoxia link.
Many others: ELL2, MYB, PML, RBBP8, FLT3, KLF10/TIEG1, NUMB, BAG1, KIF22, SYP [UniProt].

Subcellular location

Predominantly cytoplasmic; partially nuclear. [UniProt SUBCELLULAR LOCATION: Cytoplasm. Nucleus.]
Cytoplasm/cytosol is the active compartment (is_active_in cytoplasm, IBA). Nuclear pool real
(HIPK2, transcription-factor substrates). Nucleoplasm IDA from HPA (GO_REF:0000052).

Apoptosis / tumor suppression / nervous system

p53-inducible; originally identified in apoptosis and tumor suppression [UniProt ref 8799150].
Promotes apoptosis (intrinsic pathway via XIAP; POSH/JNK). [PMID:21185211; PMID:16230351 POSH-JNK]
Nervous system development / axon guidance via DCC regulation. [PMID:9334332; PMID:9403064]

Annotation-call reasoning

Core MF: ubiquitin protein ligase activity (GO:0061630) / ubiquitin-protein transferase
(GO:0004842) — genuine RING E3, catalytic. ACCEPT.
ubiquitin conjugating enzyme binding (GO:0031624) — ACCEPT (E2 binding is core to RING mechanism).
zinc ion binding (GO:0008270) — ACCEPT (RING + Zn fingers; structurally demonstrated).
proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161) — ACCEPT core BP.
cytoplasm/cytosol — ACCEPT (active site). nucleus/nucleoplasm — KEEP_AS_NON_CORE (real secondary).
canonical Wnt signaling (GO:0060070) — KEEP_AS_NON_CORE (downstream pathway; AXIN1 substrate).
apoptosis terms — KEEP_AS_NON_CORE (downstream processes of substrate degradation).
amyloid fibril formation (GO:1990000) — Reactome/ARBA: alpha-synuclein context; KEEP_AS_NON_CORE
(this is the substrate's aggregation behavior, not SIAH1's intrinsic function). Borderline
over-annotation but Reactome TAS curates SIAH1 in the SNCA amyloid pathway.
protein binding (GO:0005515) bare IPI — KEEP_AS_NON_CORE per curation guidelines.
identical protein binding (GO:0042802) — ACCEPT/KEEP_AS_NON_CORE: SIAH1 homodimerizes (real),
but it is a specific informative interaction; keep as non-core (dimerization supports function).
nervous system development / axon guidance / morphogenesis — KEEP_AS_NON_CORE (pleiotropic dev roles).
protein destabilization (GO:0031648) — KEEP_AS_NON_CORE (consequence of degradation activity).
neuron apoptotic process — KEEP_AS_NON_CORE.

Citation issue (PMID:11863358)

The GOA zinc ion binding (IDA) annotation cites PMID:11863358 "An anthropoid-specific
locus of orphan C to U RNA-editing enzymes on chromosome 22." The cached (abstract-only)
entry is entirely about APOBEC C-to-U RNA-editing enzymes and contains ZERO mention of
SIAH1/seven-in-absentia. This looks like a wrong-identifier citation. Per project
guardrails I do not REMOVE an experimental IDA on the basis of incomplete cached evidence;
marked UNDECIDED and flagged correctness=WRONG_IDENTIFIER. SIAH1 zinc binding itself is
well supported by the structural study PMID:16085652 (RING + SIAH-type Zn fingers).

Pn Notes

(SIAH1-pn-notes.md)

SIAH1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8IUQ4
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-14
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/SIAH1/SIAH1-ai-review.yaml
AIGR review HTML: missing - genes/human/SIAH1/SIAH1-ai-review.html
Gene notes: present - genes/human/SIAH1/SIAH1-notes.md
GOA TSV: present - genes/human/SIAH1/SIAH1-goa.tsv
UniProt record: present - genes/human/SIAH1/SIAH1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/SIAH1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/SIAH1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 34; KEEP_AS_NON_CORE: 39; MARK_AS_OVER_ANNOTATED: 2

PN Consistency Summary

Consistency: Review YAML, notes and PN UPS annotation are fully aligned on the catalytic RING E3 identity (GO:0061630 core; EC 2.3.2.27; zinc fingers; homodimer). The ALP/mitophagy PN row is the one divergence: the review contains NO autophagy/mitophagy annotation, GOA has none, and SIAH1-uniprot.txt mentions SNCA/SNCAIP ubiquitination but not mitophagy or PINK1. The deep-research notes likewise do not mention the PINK1-SIAH1-synphilin mitophagy pathway.
PN story / NEW pressure: PN asserts a PRKN-independent PINK1-SIAH1-SNCAIP mitophagy role absent from existing GO. The supporting paper (Szargel et al. 2016 HMG, "PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway") is real and not in the publications cache or the review. GO:0000423 mitophagy is a verified real term (OLS). This is a defensible ADD candidate, but it rests on a single primary paper not yet read in full and not in cache — propose as a NEW annotation pending full-text verification, not a slam-dunk.
Evidence alignment: Strong overlap on the UPS side conceptually but NOT by PMID — the PN UPS row cites only "19489725 / rev" (a review), while the review's ligase support is PMID:9334332/19224863/28546513/33591310. The PN ALP row cites the Szargel HMG mitophagy paper + a tandfonline PRKN-independent-mitophagy review, neither of which appears in the review references. Divergence is total on the mitophagy evidence.
Verdict: Catalytic E3 mapping consistent and correct; mitophagy is a genuine NEW-GO opportunity (GO:0000423, verified) currently missing from review and GOA. The PMID:11863358 zinc-binding citation is correctly flagged WRONG_IDENTIFIER in reference_review (APOBEC RNA-editing paper, zero SIAH1 mention); SIAH1 zinc binding itself is correct (PMID:16085652), so ACCEPT of the term is sound — no change to that call.

Full Consistency Review

UniProt: Q8IUQ4 · batch: proteostasis-batch-2026-06-14 · review status: COMPLETE (dual UPS + ALP placement)
PN placement: UPS row E3 ubiquitin and UBL ligases|RING|SIAH / SINA|SIA TRAF-like and ALP row Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy|PINK/PRKN pathway ; PN-node mapping: UPS group mapped/ok_for_propagation = GO:0061630 ubiquitin protein ligase activity (already_in_goa_exact); ALP type mapped/ok_for_propagation = GO:0000423 mitophagy (flagged new_to_goa).
Consistency: Review YAML, notes and PN UPS annotation are fully aligned on the catalytic RING E3 identity (GO:0061630 core; EC 2.3.2.27; zinc fingers; homodimer). The ALP/mitophagy PN row is the one divergence: the review contains NO autophagy/mitophagy annotation, GOA has none, and SIAH1-uniprot.txt mentions SNCA/SNCAIP ubiquitination but not mitophagy or PINK1. The deep-research notes likewise do not mention the PINK1-SIAH1-synphilin mitophagy pathway.
PN story / NEW pressure: PN asserts a PRKN-independent PINK1-SIAH1-SNCAIP mitophagy role absent from existing GO. The supporting paper (Szargel et al. 2016 HMG, "PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway") is real and not in the publications cache or the review. GO:0000423 mitophagy is a verified real term (OLS). This is a defensible ADD candidate, but it rests on a single primary paper not yet read in full and not in cache — propose as a NEW annotation pending full-text verification, not a slam-dunk.
Mapping strategy: This gene does not require changing either node's status. The UPS group mapping to GO:0061630 is exact and correct (catalytic ligase kept as core, per the SIAH1 KEY PATTERN). The ALP type→GO:0000423 propagation is reasonable IF the Szargel evidence is verified; scope ok_for_propagation is acceptable. The zinc ion binding IDA was ACCEPTed and the wrong citation already flagged correctly (see below) — no re-mapping needed.
Evidence alignment: Strong overlap on the UPS side conceptually but NOT by PMID — the PN UPS row cites only "19489725 / rev" (a review), while the review's ligase support is PMID:9334332/19224863/28546513/33591310. The PN ALP row cites the Szargel HMG mitophagy paper + a tandfonline PRKN-independent-mitophagy review, neither of which appears in the review references. Divergence is total on the mitophagy evidence.
Verdict: Catalytic E3 mapping consistent and correct; mitophagy is a genuine NEW-GO opportunity (GO:0000423, verified) currently missing from review and GOA. The PMID:11863358 zinc-binding citation is correctly flagged WRONG_IDENTIFIER in reference_review (APOBEC RNA-editing paper, zero SIAH1 mention); SIAH1 zinc binding itself is correct (PMID:16085652), so ACCEPT of the term is sound — no change to that call.
Recommended edits: [YAML] Add a mitophagy annotation GO:0000423 (NEW, qualifier involved_in) for the PINK1-SIAH1-SNCAIP PRKN-independent pathway, supported_by the Szargel et al. 2016 HMG paper — first fetch/verify the PMID (Szargel HMG 2016; cache currently lacks it) and add it to references; mark UNDECIDED→NEW only after full-text confirmation. [REF] Keep the existing PMID:11863358 WRONG_IDENTIFIER flag (no change); optionally re-anchor the zinc IDA's primary support note to PMID:16085652.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-14
review_yaml: genes/human/SIAH1/SIAH1-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | Mitophagy | PINK/PRKN pathway

UniProt: Q8IUQ4
In branches: ALP, UPS
Notes: Part of a PINK1-SIAH1-SNCAIP complex that induces mitophagy in a PRKN-independent manner.
PN references (titles):
- Full article: Regulation of PRKN-independent mitophagy (tandfonline.com)
- PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway | Human Molecular Genetics | Oxford Academic (oup.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy|PINK/PRKN pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0000423 mitophagy]
  rationale: The PN marking category for mitophagy captures upstream cargo-marking steps that commit mitochondrial substrates to the mitophagy pathway. That supports propagation to mitophagy.
- [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | SIAH / SINA | SIA TRAF-like

UniProt: Q8IUQ4
In branches: ALP, UPS
Signature domains: IPR001841
Auxiliary domains: IPR013010, IPR018121
PN references (titles):
- 19489725 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|SIAH / SINA|SIA TRAF-like
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|SIAH / SINA
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

GO:0000423 mitophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy
GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

SIAH1

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

SIAH1 (seven in absentia homolog 1) review notes

Domain architecture

Core molecular function

Substrates / processes (the heart of SIAH1 biology)

Subcellular location

Apoptosis / tumor suppression / nervous system

Annotation-call reasoning

Citation issue (PMID:11863358)

Pn Notes

SIAH1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | Mitophagy | PINK/PRKN pathway

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | SIAH / SINA | SIA TRAF-like

Projected GO annotations (2)

Note

📄 View Raw YAML