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.
| 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/Ξ²-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/Ξ²-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/Ξ²-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 Ξ²-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/Ξ²-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/Ξ²-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 |
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Download this section (compressed HTML)Q: 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)?
Q: 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?
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.
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