Affinage

SIAH2

E3 ubiquitin-protein ligase SIAH2 · UniProt O43255

Length
324 aa
Mass
34.6 kDa
Annotated
2026-06-10
96 papers in source corpus 45 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIAH2 is a RING-finger E3 ubiquitin ligase that operates as a central signaling node, recognizing degron motifs on a broad array of substrates and driving their proteasomal degradation to integrate hypoxic, metabolic, DNA-damage, circadian, and developmental outputs (PMID:15210114, PMID:23518348, PMID:25438054). Its best-defined role is in the hypoxic response: SIAH2 (with SIAH1a) targets the prolyl hydroxylases PHD1/PHD3 for degradation, with selectivity for the most active PHD3 pool, thereby stabilizing HIF-1α under hypoxia (PMID:15210114, PMID:16958618). Through this and parallel arms, SIAH2 reprograms tumor metabolism and growth—degrading OGDH2 to shift glutamine flux, NRF1 to enforce the Warburg effect, and Sprouty2 to activate Ras/MAPK (PMID:18946040, PMID:24506869, PMID:30833558)—and it inactivates the Hippo pathway by ubiquitinating LATS2 (scaffolded by Zyxin) to activate YAP, which in turn feeds back to stabilize HIF-1α (PMID:25438054, PMID:27030211). SIAH2 substrates extend across diverse processes: it degrades AKAP121 to license hypoxic mitochondrial fission (PMID:22099302), the circadian regulator RevErbα to set period length (PMID:26392558), the androgen receptor's NCOR1-bound repressive pool to de-repress AR targets in prostate cancer (PMID:23518348), TRAF2 to modulate JNK/NF-κB and apoptosis under stress (PMID:12411493), and CtIP to enable DNA double-strand break end resection and homologous recombination (PMID:36155803). SIAH2's own abundance and activity are tightly regulated: multiple kinases including HIPK2, DYRK2, CHK2, Src, and MRCKβ phosphorylate it to alter stability and substrate targeting, often within reciprocal loops in which SIAH2 degrades the same kinase (HIPK2, DYRK2, CHK2, PLK3) (PMID:19043406, PMID:22878263, PMID:26751770, PMID:28515325); the deubiquitinase USP13 and scaffold AKR1C3 oppose its autodegradation to stabilize it (PMID:21659512, PMID:26160177); and HDAC1/2-controlled acetylation governs its levels (PMID:40877230). In development, SIAH2 controls cerebellar granule neuron ciliogenesis and germinal-zone exit downstream of Shh/Ras-MAPK and via regulation of DCC surface recruitment (PMID:33082319, PMID:39774925), and it drives adipogenesis through degradation of antiadipogenic ZFP521 and modulation of Wnt/β-catenin signaling (PMID:33155406, PMID:27864366).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 High

    Established SIAH2 as a stress-inducible E3 ligase coupling protein degradation to apoptotic and inflammatory signaling, the first defined substrate context for the ligase.

    Evidence In vitro ubiquitylation with RING-mutant controls plus TRAF2 half-life in Siah2-null MEFs under TNF-α/actinomycin D stress

    PMID:12411493

    Open questions at the time
    • Did not define the TRAF2 degron motif
    • Stress-specificity of substrate recognition mechanism unresolved
  2. 2004 High

    Placed SIAH2 upstream of HIF-1α by showing it degrades the prolyl hydroxylases PHD1/PHD3, defining its core role in oxygen sensing.

    Evidence Siah2-null and Siah1a/2-null MEFs with PHD3 half-life assays, RNAi rescue epistasis, and in vivo hypoxia challenge

    PMID:15210114

    Open questions at the time
    • Direct PHD degron not yet mapped
    • Did not address how hypoxia regulates SIAH2 activity itself
  3. 2007 High

    Explained PHD substrate selectivity—SIAH2 preferentially degrades the active monomeric PHD3 pool lacking an N-terminal extension, refining the molecular basis of HIF regulation.

    Evidence Domain-deletion mutants of PHD1/2/3, size-exclusion fractionation, co-localization, and hydroxylation activity assays

    PMID:16958618

    Open questions at the time
    • Structural basis of degron recognition not solved
    • Xenopus ortholog data (idx 43) showed divergent PHD selectivity
  4. 2008 High

    Demonstrated SIAH2 functions in cancer through two parallel substrate arms (HIF-1α via PHD3, Ras/MAPK via Sprouty2) and revealed the first kinase autoregulatory loop with HIPK2.

    Evidence Syngeneic melanoma models with dominant-negative RING mutant and competing peptide; phospho-site mapping and Co-IP for HIPK2

    PMID:18946040 PMID:19043406

    Open questions at the time
    • Quantitative contribution of each substrate arm to tumor phenotype not separated mechanistically
    • How hypoxia switches the HIPK2-SIAH2 binding state unresolved
  5. 2009 Medium

    Defined how SIAH2 abundance and substrate-binding are controlled—via a conserved degron in MYPT1, pharmacological RING inhibition by menadione—expanding its substrate range and revealing druggability.

    Evidence Degron motif mutagenesis and Co-IP for MYPT1; high-throughput ubiquitin ligase activity assay with Siah-KO controls for menadione

    PMID:19712206 PMID:19744480

    Open questions at the time
    • Menadione selectivity and mechanism of RING inhibition not fully defined
    • MYPT1 degradation physiological context unestablished
  6. 2011 High

    Revealed extensive post-translational control of SIAH2 stability (USP13 ubiquitin-binding stabilization, Ski scaffolding, Src tyrosine phosphorylation) and expanded substrates into telomere maintenance and transcriptional regulation (TIN2, HDAC3, C/EBPδ).

    Evidence USP13 domain mutants and substrate level assays; in vitro ubiquitylation of purified TIN2; Co-IP and Src kinase assays

    PMID:20691163 PMID:21659512 PMID:22037769 PMID:22064479

    Open questions at the time
    • Integration of competing stabilizing and destabilizing inputs not modeled
    • Physiological triggers for telomeric TIN2 remodeling unclear
  7. 2011 High

    Linked SIAH2 to mitochondrial dynamics and ischemic protection by showing AKAP121 degradation licenses Drp1-mediated fission under hypoxia.

    Evidence Siah2-null cells and mice, Drp1-Fis1 Co-IP, mitochondrial imaging, and myocardial infarction model

    PMID:22099302

    Open questions at the time
    • AKAP121 degron not mapped
    • Generality across cell types beyond cardiomyocytes not established
  8. 2012 Medium

    Extended SIAH2 into adipogenesis and circadian/metabolic transcription factor turnover (PPARγ, DYRK2) and added a second kinase reciprocal loop with DYRK2 affecting localization and p53 signaling.

    Evidence RNAi screen and Co-IP for PPARγ; in vitro kinase phospho-site mapping and ubiquitination assays for DYRK2

    PMID:22294748 PMID:22878263

    Open questions at the time
    • Subcellular localization control by phosphorylation not structurally resolved
    • Ligand-dependence of PPARγ recognition mechanism unclear
  9. 2013 High

    Broadened SIAH2 substrate scope across nuclear receptor signaling, oxidative/hypoxic stress, and epithelial architecture (AR-NCOR1, Nrf2 Keap1-independent, ASPP2).

    Evidence Co-IP, ubiquitination assays, degron mapping, Keap1-deletion Nrf2 mutants, and 3D organotypic culture; TRAMP mouse NE tumor model for HIF-1α/FoxA2/p300

    PMID:20609350 PMID:23518348 PMID:23644657 PMID:23645672

    Open questions at the time
    • Selectivity for NCOR1-bound AR pool not structurally explained
    • How hypoxia routes Nrf2 to SIAH2 versus Keap1 unresolved
  10. 2014 High

    Connected SIAH2 to metabolic reprogramming and Hippo pathway inactivation under hypoxia (OGDH2, LATS2/YAP, TYK2/STAT3), positioning it downstream of HIF-1 and p53.

    Evidence Ubiquitination-site mutagenesis (OGDH2 K336A) with metabolic flux; Co-IP and xenograft epistasis for LATS2/YAP; protein stability and STAT phospho-assays for TYK2

    PMID:24506869 PMID:24833526 PMID:25438054

    Open questions at the time
    • Feed-forward YAP–HIF1α loop kinetics not dissected
    • TYK2 ubiquitination not reconstituted in vitro
  11. 2015 Medium

    Defined SIAH2 control of the circadian clock and a non-enzymatic scaffolding feedback that stabilizes the ligase (RevErbα degradation; AKR1C3 stabilization).

    Evidence E3 ligase functional screen with circadian period measurement; Co-IP and self-ubiquitination assays with catalytically inactive AKR1C3

    PMID:26160177 PMID:26392558

    Open questions at the time
    • RevErb degron not mapped
    • AKR1C3 scaffolding stoichiometry and binding interface undefined
  12. 2016 Medium

    Identified scaffold-assisted and competitively-regulated substrate engagement (Zyxin for LATS2; CHK2 reciprocal kinase loop; EAF2/ELL1 competition) consolidating DNA-damage and Hippo regulation.

    Evidence Ternary complex Co-IP and ubiquitination assays; CHK2 kinase-inactive/phospho mutants under etoposide; EAF2 K81R and ELL1 competition assays

    PMID:26751770 PMID:27030211 PMID:27058417

    Open questions at the time
    • How scaffolds dictate substrate choice mechanistically unclear
    • CHK2 interaction disruption signal under DNA damage not defined
  13. 2017 Medium

    Added further kinase reciprocal loops and stabilizing cofactors controlling AR and hypoxia outputs (PLK3 polo-box engagement; DHX15 ATPase-independent stabilization).

    Evidence Co-IP, polo-box domain mapping, kinase-dead PLK3 mutants; yeast screen and ATPase-dead DHX15 with AR ubiquitination

    PMID:28515325 PMID:28991234

    Open questions at the time
    • USP28 contribution to PLK3 regulation not resolved
    • Mechanism by which DHX15 enhances E3 activity unclear
  14. 2019 High

    Established SIAH2 as a driver of the Warburg effect and pro-tumor macrophage polarization through site-specific NRF1 degradation.

    Evidence SIAH2 KO with NRF1 K230R rescue, mitochondrial gene expression, metabolic assays, and TAM polarization

    PMID:30833558

    Open questions at the time
    • NRF1 degron sequence not defined
    • Tumor-cell-intrinsic versus microenvironmental effects not fully separated
  15. 2020 Medium

    Expanded SIAH2 into immune-cell cycling, neuronal mitochondrial protection, ferroptosis/redox control, and developmental ciliogenesis (p27 in Tregs, NCX3, HO-1/GPX4, granule-neuron cilia).

    Evidence Siah2-null tumor models with Treg cell-cycle profiling and anti-PD-1 combination; neuronal OGD with NCX3 Co-IP; RING-mutant HO-1 rescue; cerebellar granule neuron ciliogenesis assays

    PMID:31911617 PMID:32042051 PMID:32164721 PMID:33082319

    Open questions at the time
    • Whether p27 is a direct SIAH2 substrate not biochemically confirmed
    • Tissue-specific substrate selection across these contexts unexplained
  16. 2022 Medium

    Linked SIAH2 to homologous recombination and DNA-replication recovery via non-degradative CtIP ubiquitination, and to DBC1 turnover, glycolysis, and adipogenesis, illustrating both degradative and recruitment-type ubiquitin functions.

    Evidence CtIP lysine mutants with HR and fork-recovery assays; OTUD5-balanced DBC1 degradation with double-KO rescue; WNK1 ubiquitination with CBX2/EZH2 promoter ChIP; MRCKβ phospho-loop

    PMID:33536006 PMID:35913115 PMID:36155803 PMID:36780970

    Open questions at the time
    • Non-degradative (recruitment) versus degradative ubiquitin signals on CtIP not fully distinguished
    • Linkage type of CtIP ubiquitination unspecified
  17. 2025 Medium

    Resolved acetylation-based control of SIAH2 stability and defined a therapeutically actionable degron in oncogenic JAK2V617F, plus developmental DCC/Netrin guidance and ferroptosis/immune regulation roles.

    Evidence HDAC1/2 KO and SIAH2 KO MPN cells with UBCH8-JAK2V617F complex Co-IP and degron mapping; genetic epistasis for DCC/Pard3/JamC; ACSL4 and HBx K48 ubiquitination assays

    PMID:38842124 PMID:38842200 PMID:39774925 PMID:40877230 PMID:42036676

    Open questions at the time
    • Structural details of acetylation-controlled stability unresolved
    • How a single ligase achieves degron-level selectivity across this many substrates remains unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • The unifying question of how SIAH2 achieves substrate selectivity and is differentially activated across hypoxic, metabolic, DNA-damage, circadian, and developmental contexts remains open.
  • No structure of SIAH2 bound to a physiological substrate degron
  • No comprehensive map of which kinase/acetylation inputs dominate in each tissue
  • Degron consensus across the substrate set not derived

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-73894 DNA Repair 2 R-HSA-9909396 Circadian clock 1
Partners
AKR1C3CHK2DYRK2HIPK2LATS2PLK3USP13ZYX

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Siah2 (together with Siah1a) targets PHD1 and PHD3 (prolyl hydroxylases) for proteasome-dependent ubiquitin-mediated degradation under hypoxia, thereby increasing HIF1α abundance. Siah2-null fibroblasts show prolonged PHD3 half-life and lower HIF1α during hypoxia; HIF1α induction is fully abolished in Siah1a/2 double-null cells but rescued by PHD3 RNAi knockdown, placing Siah2 upstream of PHD3 in the HIF1α stabilization pathway. Siah2-null and Siah1a/2-null mouse embryo fibroblasts, protein half-life assays, RNAi rescue epistasis, in vivo hypoxia challenge in Siah2-null mice Cell High 15210114
2002 Siah2 targets TRAF2 for ubiquitylation and proteasome-dependent degradation specifically under stress conditions (TNF-α + actinomycin D). RING-mutant Siah2 loses this activity. Siah2-mediated TRAF2 degradation attenuates JNK activity and NF-κB transcriptional activation and promotes apoptosis. In vitro ubiquitylation assay with wild-type vs. RING-mutant Siah2, TRAF2 half-life comparison in Siah2−/− vs. wild-type MEFs under stress, JNK and NF-κB reporter assays, apoptosis assay The EMBO journal High 12411493
2007 Siah2 preferentially degrades PHD3 over PHD1/PHD2 because PHD3 lacks the N-terminal extension present in PHD1/2; deletion of this extension from PHD1/2 renders them susceptible to Siah2-mediated degradation. PHD3 forms homo- and hetero-multimers; the lower-molecular-mass (monomeric) form co-localizes with Siah2 and has higher HIF-1α hydroxylation activity, indicating Siah2 limits the most active PHD3 pool. Domain-deletion mutants of PHD1/2/3, size-exclusion chromatography fractionation under normoxia/hypoxia, co-localization of PHD3 with Siah2, hydroxylation activity assays The Biochemical journal High 16958618
2008 HIPK2 phosphorylates Siah2 at Ser26, Ser28, and Ser68, weakening their mutual binding and destabilizing Siah2 under normoxia. Under hypoxia, HIPK2–Siah2 interaction increases markedly, leading to efficient polyubiquitylation and proteasomal degradation of HIPK2 by Siah2. Hypoxia-induced HIPK2 elimination is markedly reduced in Siah2-deficient cells, establishing an inducible autoregulatory loop. Co-immunoprecipitation, phospho-site mapping, Siah2-deficient cell lines, proteasome inhibitor experiments, reporter assays for hypoxia-induced gene expression Nature cell biology High 19043406
2008 Siah2 regulates tumorigenesis and metastasis through two distinct substrate arms: (1) PHD3 degradation stabilizes HIF-1α to promote metastasis; (2) Siah2-mediated degradation of Sprouty2 (a negative regulator of Ras/MAPK) promotes tumorigenesis. A competing peptide blocking Siah2 substrate binding reduces metastasis via HIF-1α, while dominant-negative RING mutant Siah2 primarily reduces tumorigenesis via Sprouty2. Syngeneic mouse melanoma model, dominant-negative Siah2 RING mutant, competing substrate-binding peptide, HIF-1α and Sprouty2 protein level analysis, tumor/metastasis assays Proceedings of the National Academy of Sciences of the United States of America Medium 18946040
2009 Siah2 interacts with and ubiquitinates MYPT1 (myosin phosphatase target subunit 1), targeting it for proteasomal degradation. The interaction requires the substrate-binding domain of Siah2 (aa 116–324) and a degenerate Siah-binding motif (RLAYVAP, aa 493–499) in MYPT1, conserved from fish to humans. Co-immunoprecipitation, domain-deletion mapping, mutational analysis of degron motif, proteasome inhibitor rescue Experimental cell research Medium 19744480
2009 Menadione (vitamin K3) inhibits Siah2 ubiquitin ligase activity (self-ubiquitination) in a RING-dependent manner, increasing levels of Siah2 substrates PHD3 and Sprouty2 and decreasing HIF-1α and pERK. Menadione no longer affects PHD3 or Sprouty2 in Siah-KO cells, confirming Siah2 dependence. The effect is not mediated by ROS. High-throughput electrochemiluminescence-based ubiquitin ligase activity assay, Siah-KO cell controls, free-radical scavenger controls, xenograft melanoma tumor growth assay Pigment cell & melanoma research Medium 19712206
2010 Siah2-dependent stabilization of HIF-1α enables cooperation between HIF-1α and the transcription factor FoxA2; their complex recruits p300 to transactivate specific target genes (Hes6, Sox9, Jmjd1a) required for neuroendocrine prostate tumor development. Formation of NE tumors in the TRAMP mouse model is suppressed in Siah2-null mice. Siah2-null TRAMP mice, co-immunoprecipitation of HIF-1α/FoxA2/p300 complex, target gene expression analysis, RNAi knockdowns Cancer cell High 20609350
2011 Siah2 ubiquitin ligase controls AKAP121 protein levels; reduced AKAP121 availability relieves PKA-dependent inhibitory phosphorylation of Drp1 and increases Drp1–Fis1 interaction, resulting in mitochondrial fission under hypoxia. Siah2-null cells retain high AKAP121 levels, attenuate fission, and show reduced apoptosis under simulated ischemia. Siah2-null mice have reduced infarct size after myocardial infarction. Siah2−/− cells and mice, AKAP121 overexpression/knockdown, Co-IP of Drp1-Fis1 complex, mitochondrial morphology imaging, cardiomyocyte apoptosis assay, myocardial infarction model Molecular cell High 22099302
2011 USP13 deubiquitinase stabilizes Siah2 by binding ubiquitinated Siah2 and inhibiting its autodegradation, thereby also attenuating Siah2's ability to ubiquitinate and degrade its substrates PHD3 and Sprouty2. Critically, USP13's effect on Siah2 depends on its ubiquitin-binding domains (UBP and UBA), not its catalytic isopeptidase activity—mutations in catalytic sites do not abolish the effect. USP13 overexpression/shRNA knockdown, Siah2 protein stability assays, USP13 domain mutants (catalytic vs. ubiquitin-binding), substrate (PHD3, Spry2) level analysis, Co-IP The Journal of biological chemistry High 21659512
2011 Siah2 interacts with C/EBPδ (but not C/EBPβ) and promotes its polyubiquitination and proteasomal degradation. Src tyrosine kinase phosphorylates SIAH2 in vitro and leads to SIAH2 tyrosine phosphorylation and activation in breast tumor cell lines, placing Src upstream of Siah2 in regulation of C/EBPδ abundance. In vitro Src kinase assay with SIAH2, Co-IP of SIAH2 with C/EBPδ/C/EBPβ, ubiquitination assays, degradation-resistant C/EBPδ mutants, Src inhibitor (bosutinib) treatment Molecular and cellular biology High 22037769
2011 TIN2 (telomere shelterin component) binds Siah2 and is ubiquitylated in vivo and directly ubiquitylated by purified Siah2 in vitro. Siah2 depletion stabilizes TIN2 protein. Siah2 overexpression causes TIN2 loss from telomeres dependent on the RING domain, whereas TRF1 and TRF2 remain at telomeres but TPP1 is displaced, indicating a distinct remodeling outcome from RNAi-mediated TIN2 depletion. In vitro ubiquitylation with purified proteins, Co-IP, Siah2 depletion/overexpression, RING-domain mutant, telomere chromatin immunoprecipitation/immunofluorescence Molecular and cellular biology High 22064479
2011 Siah2 mediates proteasomal degradation of HDAC3. Ski protein interacts with Siah2, stabilizes Siah2 protein (consistent with Ski inhibiting Siah2 autoubiquitination activity), and consequently stabilizes HDAC3. Only Ski truncation mutants that form a complex with Siah2 can stabilize HDAC3 levels. Reciprocal co-immunoprecipitation of Ski–Siah2 complex, Ski truncation mutant analysis, HDAC3 protein level assays under Siah2 overexpression ± Ski co-expression Biochemical and biophysical research communications Medium 20691163
2012 SIAH2 ubiquitinates and promotes proteasomal degradation of PPARγ in a ligand-dependent manner in adipocytes. An RNAi screen identified Siah2 as one of five RING-type E3 ligases affecting PPARγ levels. Siah2 expression increases during adipogenesis, PPARγ co-immunoprecipitates with Siah2 during adipogenesis, and Siah2 is required for adipogenesis. RNAi screen, Co-IP of PPARγ–Siah2 in adipocytes, PPARγ ubiquitylation assay, Siah2 knockdown adipogenesis assay Endocrinology Medium 22294748
2012 DYRK2 phosphorylates SIAH2 at five residues (Ser16, Thr26, Ser28, Ser68, Thr119). Phosphomimetic SIAH2 shows altered subcellular localization and increased PHD3-degrading/HIF-1α-activating activity. Conversely, SIAH2 mediates DYRK2 polyubiquitination and proteasomal degradation, especially under hypoxia, creating a mutual regulation loop that also impairs DYRK2-mediated p53 Ser46 phosphorylation. Phospho-site mapping by in vitro kinase assay, phosphomimetic/phospho-mutant Siah2 constructs, subcellular fractionation, DYRK2 ubiquitination assay, SIAH2 knockdown, p53 phosphorylation analysis Journal of molecular cell biology Medium 22878263
2013 Siah2 targets NCOR1-bound, transcriptionally inactive androgen receptor (AR) for ubiquitin-dependent degradation, selectively de-repressing AR target genes involved in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo. Co-IP of Siah2–AR–NCOR1 complex, ubiquitination assay, AR target gene expression after Siah2 knockdown/overexpression, in vivo castration + Siah2 inhibition model Cancer cell High 23518348
2013 Siah2 interacts with and ubiquitinates Nrf2, targeting it for proteasomal degradation during hypoxia via a Keap1-independent mechanism. Siah2 knockdown prevents hypoxic Nrf2 suppression; a Nrf2 mutant lacking the Keap1-binding domain is still degraded by Siah2. PKC phosphorylates Nrf2 Ser40 during hypoxia, but Siah2-mediated degradation is independent of this phosphorylation status. Co-IP of Siah2–Nrf2 interaction, Siah2 knockdown, ubiquitination assay with Nrf2 phospho-mutants, Keap1 domain-deletion Nrf2 mutant, proteasome inhibitor rescue The Journal of biological chemistry Medium 23645672
2013 Siah2 controls ASPP2 protein availability under hypoxia: LC-MS/MS identified ASPP2 as a Siah2-interacting protein; biochemical analysis confirmed the interaction and mapped degron motifs in ASPP2 required for Siah2-mediated ubiquitination and degradation. Inhibition of Siah2 increases ASPP2 levels, enhancing tight junction integrity and polarized architecture in 3D organotypic culture. LC-MS/MS proteomics pulldown of Siah2 interactors, Co-IP, degron motif mapping, ASPP2 ubiquitination assay, Siah2 KD/OE in 3D organotypic culture with tight junction and polarity readouts Oncogene Medium 23644657
2014 SIAH2 ubiquitinates and promotes proteasomal degradation of OGDH2 (the 48-kDa E1 splice variant of the α-ketoglutarate dehydrogenase complex) under hypoxia downstream of HIF-1 activation. Mutation of the ubiquitinated lysine (K336A) in OGDH2 reverses the hypoxic drop in αKGDH activity and shifts glutamine metabolism from reductive carboxylation to oxidation. SIAH2 knockdown, OGDH2 ubiquitination assay, K336A ubiquitination-site mutant, αKGDH activity assay, metabolic flux analysis, xenograft growth assay Cell metabolism High 24506869
2014 SIAH2 ubiquitinates and destabilizes LATS2 (a core Hippo pathway kinase) under hypoxia, activating YAP. Loss of SIAH2 suppresses tumorigenesis in a LATS2-dependent manner in xenograft models. YAP subsequently forms a complex with HIF1α and is required for HIF1α stability and function. Co-IP, ubiquitination assay, SIAH2 KO/KD with LATS2-dependent rescue, xenograft tumor model, Co-IP of YAP–HIF1α complex Nature cell biology High 25438054
2014 SIAH2 promotes proteasomal degradation of TYK2, thereby suppressing TYK2-mediated STAT3 activation in lung carcinoma cells. p53 activation induces SIAH2 expression, leading to TYK2 depletion and abrogation of STAT1/STAT3 tyrosine phosphorylation. SIAH2 overexpression/knockdown, TYK2 protein stability assay, STAT3 phosphorylation analysis, p53 activation experiments Oncotarget Medium 24833526
2015 Siah2 ubiquitinates and promotes degradation of RevErbα (and RevErbβ), a key constituent of the mammalian circadian clock. Siah2 siRNA depletion stabilizes endogenous RevErbα, delays its circadian degradation, and lengthens circadian period length. Cell-based E3 ligase functional screen for RevErbα stability, Siah2 overexpression/siRNA, endogenous RevErbα stability assays, circadian period measurement Proceedings of the National Academy of Sciences of the United States of America Medium 26392558
2015 AKR1C3 (steroidogenic enzyme) binds Siah2 and inhibits Siah2 self-ubiquitination and autodegradation, thereby increasing Siah2 protein levels. This positive feedback stabilizes Siah2 and enhances Siah2-dependent AR activation in prostate cancer cells. Both wild-type and catalytically inactive AKR1C3 rescue Siah2 levels, indicating a non-enzymatic scaffolding role. Co-IP of AKR1C3–Siah2, Siah2 self-ubiquitination assay ± AKR1C3, catalytically inactive AKR1C3 mutant rescue, AKR1C3 knockdown/overexpression with Siah2 protein level measurement The Journal of biological chemistry Medium 26160177
2016 SIAH2 interacts with LATS2 and facilitates its ubiquitination and degradation in response to both hypoxia and TGF-β stimulation. LIM domain protein Zyxin acts as a scaffold that forms a ternary complex with Lats2 and Siah2, stabilizing their interaction. Zyxin is required for TGF-β and hypoxia-induced Lats2 downregulation and Hippo inactivation. Co-IP of Zyxin–Lats2–Siah2 ternary complex, ubiquitination assay, Zyxin depletion with LATS2/YAP phosphorylation readouts, xenograft tumorigenesis assay Nature communications Medium 27030211
2016 SIAH2 interacts with CHK2 and mediates its ubiquitination and proteasomal degradation independently of CHK2 activation status or kinase activity. CHK2 in turn phosphorylates SIAH2 at Thr26, Ser28, and Thr119, modifying Siah2's ability to regulate other substrates. In response to DNA damage (etoposide), the SIAH2–CHK2 interaction is disrupted, stabilizing CHK2. Hypoxia-induced SIAH2 elevation decreases CHK2 levels and contributes to resistance to genotoxic apoptosis. Co-IP of SIAH2–CHK2 complex, ubiquitination assay, CHK2 kinase-inactive and phospho-site mutants, SIAH2-deficient cells, etoposide DNA damage experiments, cell cycle analysis Oncogene Medium 26751770
2016 SIAH2 is expressed in adipocyte precursor cells and promotes adipogenesis by forming a complex with EBF1 and ZFP521 to enhance SIAH2-mediated ubiquitylation and degradation of the antiadipogenic ZFP521, while increasing EBF1 protein levels. Loss of Siah2 reduces Ebf1 gene expression early in adipogenesis. SIAH2 expression in PDGFRα+/SCA1+ precursor cells, Co-IP of SIAH2–EBF1–ZFP521 ternary complex, ZFP521 ubiquitylation assay, Siah2 KO primary cells Obesity (Silver Spring, Md.) Medium 33155406
2017 DHX15 forms a complex with Siah2 and AR through the AR nuclear export signal (NESAR). DHX15 stabilizes Siah2 and enhances its E3 ligase activity toward AR, independent of DHX15's ATPase activity, resulting in AR transcriptional activation. Yeast mutagenesis screen identifying DHX15, Co-IP of DHX15–Siah2–AR complex, DHX15 ATPase-dead mutant, Siah2 activity and AR ubiquitination assays, DHX15 KD xenograft Oncogene Medium 28991234
2017 SIAH2 binds to PLK3 via PLK3's polo-box domain and mediates its ubiquitination and proteasomal degradation under hypoxia/Ni(II) treatment. PLK3 in turn suppresses SIAH2 protein levels in a kinase activity-dependent manner, forming a mutual regulatory loop controlling the HIF hypoxic response. USP28 deubiquitinase may also contribute to Plk3 suppression under hypoxia. Co-IP of Siah2–Plk3, ubiquitination assay, polo-box domain mapping, kinase-dead Plk3 mutant, protein half-life assays, hypoxia and NiCl2 treatments The Journal of biological chemistry Medium 28515325
2019 SIAH2 ubiquitinates and degrades NRF1 (Nuclear Respiratory Factor 1) at lysine 230 under hypoxia, downregulating nuclear-encoded mitochondrial gene expression including pyruvate dehydrogenase beta, thereby enhancing the Warburg effect and reprogramming metabolism. SIAH2-mediated NRF1 degradation also polarizes tumor-associated macrophages toward a pro-tumor state. SIAH2 KO, NRF1 ubiquitination assay with K230 mapping, NRF1 K230R stabilization rescue, mitochondrial gene expression analysis, metabolic assays, TAM polarization assay Nature communications High 30833558
2020 Siah2 regulates Treg cell cycle progression by targeting p27 (cyclin-dependent kinase inhibitor) for degradation. In Siah2−/− mice, tumor-infiltrating Tregs show G1 arrest with elevated p27 levels, reducing Treg proliferation and tumor infiltration. Siah2 loss in host mice inhibits melanoma growth and synergizes with anti-PD-1 therapy. Siah2−/− mouse tumor model, flow cytometry of Treg cell cycle and p27 levels, in vitro T cell stimulation with Siah2 KO Tregs, anti-PD-1 combination experiment Nature communications Medium 31911617
2020 Siah2 interacts with and degrades NCX3 (Na+/Ca2+ exchanger isoform 3) at the outer mitochondrial membrane under hypoxia/OGD conditions. Siah2 knockout in neurons prevents NCX3 degradation and preserves mitochondrial dynamics (blocking Drp1-mediated fission and Mfn1 downregulation), restoring mitochondrial membrane potential, calcium handling, and ATP production during OGD. Co-immunoprecipitation of Siah2–NCX3, Siah2 KO cortical neurons, OGD model, mitochondrial membrane potential assay, calcium imaging, fusion/fission protein expression Cell communication and signaling : CCS Medium 32164721
2020 SIAH2 deletion increases HO-1 (heme oxygenase-1) protein levels in a RING-domain-dependent manner through direct interaction and proteasome-dependent degradation of HO-1. Elevated HO-1 in SIAH2 KO cells is also partly due to increased NRF2 (a known SIAH2 target), which drives HMOX1 transcription. SIAH2-deficient cells show reduced GPX4 expression and increased ferroptosis sensitivity. SIAH2 KO mice (organ-specific analysis), human SIAH2 CRISPR KO cells, RING-mutant rescue, HO-1 protein stability assay, HMOX1 mRNA analysis Scientific reports Medium 32042051
2020 Siah2 promotes adipogenesis at early progenitor commitment steps by acting upstream of BMP-4 to regulate Wnt pathway gene expression (Wnt10b), β-catenin levels, and proadipogenic factors Zfp432 and Bmp-4. In Siah2 shRNA preadipocytes, sustained β-catenin expression post-induction impairs PPARγ expression and adipocyte formation. Siah2 shRNA in 3T3-L1, Siah2 OE in non-precursor fibroblasts, Siah2−/− primary stromal cells, β-catenin depletion rescue, BMP-4 addition to KO cells, Wnt pathway gene expression The Journal of biological chemistry Medium 27864366
2020 In cerebellar granule neuron progenitors, Siah2 expression is maintained by Shh signaling via Ras/MAPK. Siah2 promotes ciliogenesis by restraining cilium disassembly. Laminin in the germinal zone microenvironment signals via integrin β1 receptors to engage Ras/MAPK and converge with Shh to drive Siah2-dependent ciliogenesis and germinal zone occupancy. Siah2 shRNA/OE in cerebellar granule neurons, Ras/MAPK inhibitor studies, integrin β1 perturbation, primary cilia length measurements, Shh signaling assays Nature communications Medium 33082319
2021 Siah2 is phosphorylated by MRCKβ at Ser6 and Thr279 in H. pylori-infected gastric epithelial cells. Phosphorylation stabilizes Siah2 and increases its tumorigenic potential. MRCKβ itself is ubiquitinated by Siah2 and undergoes proteasomal degradation upon interaction; MG132 rescues MRCKβ from Siah2-mediated degradation. Phospho-null Siah2 mutants (S6A, T279A) show reduced tumorigenicity. Co-IP + mass spectrometry identifying MRCKβ as Siah2-interacting kinase, phospho-site mutagenesis (S6A, T279A), MG132 rescue, clonogenicity and invasion assays, phospho-null stable cell lines Journal of biomedical science Medium 33536006
2022 SIAH2 interacts with and ubiquitinates CtIP at its N-terminal lysine residues, which is required for CtIP recruitment to DNA double-strand breaks (DSBs) and stalled replication forks. Mutation of key CtIP lysines or SIAH2 depletion impairs DSB end resection, homologous recombination repair, and replication fork recovery. Co-IP of SIAH2–CtIP, ubiquitination assay, CtIP lysine mutants, SIAH2 depletion, DSB end resection and HR repair assays, replication fork recovery assay Nucleic acids research Medium 36155803
2022 SIAH2 interacts with DBC1 (CCAR2) and promotes its ubiquitination and proteasomal degradation under hypoxia. OTUD5 deubiquitinase stabilizes DBC1; hypoxia promotes DBC1 interaction with SIAH2 over OTUD5, shifting the balance toward degradation. SIAH2 KO inhibits tumor cell proliferation and migration, rescued by double KO of SIAH2/CCAR2. Co-IP of SIAH2–DBC1 and OTUD5–DBC1, ubiquitination assay under hypoxia, SIAH2 KO/DBC1 double KO rescue, tissue microarray eLife Medium 35913115
2024 SIAH2 binds to and ubiquitinates HBx (Hepatitis B virus X protein) via K48-linked polyubiquitination in a manner dependent on its E3 ligase activity, promoting proteasomal degradation of HBx and inhibiting HBx-driven c-JUN pathway and HCC cell proliferation. Co-IP of SIAH2–HBx, K48-linked ubiquitination assay, SIAH2 catalytic mutant, HCC proliferation assay Journal of cellular and molecular medicine Medium 38842124
2024 SIAH2 ubiquitinates ACSL4 and promotes its degradation, thereby suppressing ferroptosis of HCC cells and attenuating CD8+ T cell-mediated anti-tumor immunity. Siah2 knockdown promotes ACSL4 levels, enhances tumor cell ferroptosis, and increases CD8+ T cell activity against HCC. Co-IP, ubiquitination assay of ACSL4, SIAH2 KD, xenograft, flow cytometry of CD8+ T cell function and ferroptosis markers Critical reviews in eukaryotic gene expression Medium 38842200
2025 HDAC1/HDAC2 control SIAH2 protein stability through acetylation. SIAH2, in conjunction with the E2 ubiquitin-conjugating enzyme UBCH8, accelerates proteasomal degradation of JAK2V617F. SIAH2 binds to a surface-exposed SIAH degron motif (VLP1002) in the catalytic domain of JAK2V617F. SIAH2 KO MPN cells are significantly less sensitive to HDAC inhibitors. HDAC1/HDAC2 genetic KO, SIAH2 KO MPN cells, Co-IP of SIAH2–UBCH8–JAK2V617F complex, degron motif identification, proteasomal degradation assay, HDACi sensitivity assay, RNA sequencing Signal transduction and targeted therapy Medium 40877230
2025 Siah2 ubiquitin ligase inhibits Dcc (Deleted in colorectal cancer) receptor surface recruitment by antagonizing the Pard3/JamC cell polarity complex in cerebellar granule neurons. This modulates Ntn1 (Netrin-1) repulsive signaling via Dcc to control germinal zone exit during neuronal differentiation. Genetic epistasis in mouse cerebellar granule neurons, Siah2 KO/OE, Pard3/JamC perturbation, Dcc surface localization assay, germinal zone exit assay Nature communications Medium 39774925
2016 SIAH2 targets EAF2 (tumor suppressor) for polyubiquitination; Co-IP demonstrates EAF2–SIAH2 binding. ELL1 (EAF2 binding partner) blocks EAF2 ubiquitination by SIAH2, providing a mechanism for EAF2 stabilization. An EAF2 K81R mutant with reduced ubiquitination is more potent at inducing apoptosis. Co-IP of EAF2–SIAH2, SIAH2-mediated EAF2 ubiquitination assay, ELL1 competition assay, K81R mutant apoptosis assay Oncotarget Medium 27058417
2010 Siah2 mediates proteasomal degradation of HDAC3. Interaction was identified biochemically; Siah2 overexpression reduces HDAC3 protein without affecting mRNA, and MG132 blocks degradation in Siah2-overexpressing cells. Co-IP of Siah2–HDAC3, Siah2 overexpression + MG132 rescue, HDAC3 mRNA vs. protein level analysis Biochemical and biophysical research communications Medium 20691163
2007 Siah2 overexpression in Xenopus embryos decreases PHD45 (PHD2 ortholog) but not PHD28 (PHD3 ortholog) protein levels, causing a small-eye phenotype. Co-overexpression of PHD47 rescues the abnormality, placing PHD protein availability downstream of Siah2 activity during embryonic development. Xenopus overexpression of xSiah2 and PHD proteins, phenotype rescue experiment Biochemical and biophysical research communications Low 17303083
2022 SIAH2 interacts with WNK1 and triggers its ubiquitination and proteasomal degradation in hepatocellular carcinoma cells. Low SIAH2 expression (suppressed by CBX2/EZH2-mediated H3K27me3 at the SIAH2 promoter) leads to WNK1 accumulation and enhanced glycolysis. Co-IP of SIAH2–WNK1, ubiquitination assay, SIAH2 OE/KO with WNK1 level readout, CBX2/EZH2 ChIP at SIAH2 promoter, glycolysis assay Experimental cell research Medium 36780970
2024 Siah2 promotes K48-linked polyubiquitination and proteasomal degradation of EPHB6. This activates RHOF, enhancing filopodia formation and HCC cell invasion and migration. Co-IP of SIAH2–EPHB6, K48-linked ubiquitination assay, SIAH2 KO/OE, RHOF and filopodia assays, clinical tissue correlation Cell & bioscience Medium 42036676

Source papers

Stage 0 corpus · 96 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell 356 15210114
2014 Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell metabolism 303 24506869
2014 Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Nature cell biology 215 25438054
2011 Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. Molecular cell 212 22099302
2010 Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer cell 206 20609350
2013 The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity. Cancer cell 141 23518348
2008 An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nature cell biology 115 19043406
2002 Stress-induced decrease in TRAF2 stability is mediated by Siah2. The EMBO journal 108 12411493
2008 The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways. Proceedings of the National Academy of Sciences of the United States of America 87 18946040
2016 Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways. Nature communications 86 27030211
2019 The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression. Nature communications 69 30833558
2009 Inhibition of Siah2 ubiquitin ligase by vitamin K3 (menadione) attenuates hypoxia and MAPK signaling and blocks melanoma tumorigenesis. Pigment cell & melanoma research 65 19712206
2012 The ubiquitin ligase Siah2 regulates PPARγ activity in adipocytes. Endocrinology 62 22294748
2003 Generation and analysis of Siah2 mutant mice. Molecular and cellular biology 60 14645526
2011 USP13 enzyme regulates Siah2 ligase stability and activity via noncatalytic ubiquitin-binding domains. The Journal of biological chemistry 57 21659512
2011 Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBPδ expression and contributes to transformation of breast tumor cells. Molecular and cellular biology 57 22037769
2017 DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor. Oncogene 52 28991234
2012 Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways. Journal of molecular cell biology 51 22878263
2007 Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2. The Biochemical journal 51 16958618
2012 Vascular normalization by loss of Siah2 results in increased chemotherapeutic efficacy. Cancer research 49 22354750
2011 The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression. Breast cancer research : BCR 47 21306611
2013 Seven in absentia homolog 2 (Siah2) protein is a regulator of NF-E2-related factor 2 (Nrf2). The Journal of biological chemistry 45 23645672
2015 Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock. Proceedings of the National Academy of Sciences of the United States of America 34 26392558
2008 Downregulation of SIAH2, an ubiquitin E3 ligase, is associated with resistance to endocrine therapy in breast cancer. Breast cancer research and treatment 34 18629630
2015 The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells. The Journal of biological chemistry 32 26160177
2014 SIAH2 antagonizes TYK2-STAT3 signaling in lung carcinoma cells. Oncotarget 31 24833526
2015 miR-335 Targets SIAH2 and Confers Sensitivity to Anti-Cancer Drugs by Increasing the Expression of HDAC3. Molecules and cells 30 25997740
2010 The Siah2-HIF-FoxA2 axis in prostate cancer – new markers and therapeutic opportunities. Oncotarget 30 21037926
2010 The Ski protein negatively regulates Siah2-mediated HDAC3 degradation. Biochemical and biophysical research communications 29 20691163
2016 CHK2 stability is regulated by the E3 ubiquitin ligase SIAH2. Oncogene 27 26751770
2012 A genome-wide association study identifies a genetic variant in the SIAH2 locus associated with hormonal receptor-positive breast cancer in Japanese. Journal of human genetics 27 22951594
2011 Possible role of death receptor-mediated apoptosis by the E3 ubiquitin ligases Siah2 and POSH. Molecular cancer 27 21586138
2016 ETS2 and Twist1 promote invasiveness of Helicobacter pylori-infected gastric cancer cells by inducing Siah2. The Biochemical journal 26 27048589
2020 Siah2 control of T-regulatory cells limits anti-tumor immunity. Nature communications 25 31911617
2011 Differential regulation of PML-RARα stability by the ubiquitin ligases SIAH1/SIAH2 and TRIAD1. The international journal of biochemistry & cell biology 24 22037423
2011 TIN2 stability is regulated by the E3 ligase Siah2. Molecular and cellular biology 24 22064479
2015 The ubiquitin ligase Siah2 regulates obesity-induced adipose tissue inflammation. Obesity (Silver Spring, Md.) 23 26380945
2009 Regulation of MYPT1 stability by the E3 ubiquitin ligase SIAH2. Experimental cell research 23 19744480
2020 SIAH2-mediated and organ-specific restriction of HO-1 expression by a dual mechanism. Scientific reports 22 32042051
2015 The Expression of the Ubiquitin Ligase SIAH2 (Seven In Absentia Homolog 2) Is Increased in Human Lung Cancer. PloS one 22 26580787
2021 Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy. Frontiers in cell and developmental biology 21 33842469
2020 Knocking-out the Siah2 E3 ubiquitin ligase prevents mitochondrial NCX3 degradation, regulates mitochondrial fission and fusion, and restores mitochondrial function in hypoxic neurons. Cell communication and signaling : CCS 21 32164721
2018 Testin and filamin-C downregulation by acetylated Siah2 increases invasiveness of Helicobacter pylori-infected gastric cancer cells. The international journal of biochemistry & cell biology 21 30063986
2013 Siah2 regulates tight junction integrity and cell polarity through control of ASPP2 stability. Oncogene 21 23644657
2017 MiR-30 Family Potentially Targeting PI3K-SIAH2 Predicted Interaction Network Represents a Novel Putative Theranostic Panel in Non-small Cell Lung Cancer. Frontiers in genetics 20 28210267
2022 Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression. eLife 19 35913115
2021 The role of Siah2 in tumorigenesis and cancer therapy. Gene 19 34687788
2017 Mutual regulation between Polo-like kinase 3 and SIAH2 E3 ubiquitin ligase defines a regulatory network that fine-tunes the cellular response to hypoxia and nickel. The Journal of biological chemistry 19 28515325
2019 Inhibition of Siah2 ubiquitin ligase ameliorates monocrotaline-induced pulmonary arterial remodeling through inactivation of YAP. Life sciences 18 31837334
2018 PIWIL2 suppresses Siah2-mediated degradation of HDAC3 and facilitates CK2α-mediated HDAC3 phosphorylation. Cell death & disease 18 29555935
2015 Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer. International journal of clinical and experimental pathology 17 26191134
2020 miR-146b-5p regulates bone marrow mesenchymal stem cell differentiation by SIAH2/PPARγ in aplastic anemia children and benzene-induced aplastic anemia mouse model. Cell cycle (Georgetown, Tex.) 16 32840137
2020 Siah2 integrates mitogenic and extracellular matrix signals linking neuronal progenitor ciliogenesis with germinal zone occupancy. Nature communications 16 33082319
2018 Inhibition of Siah2 Ubiquitin Ligase by Vitamin K3 Attenuates Chronic Myeloid Leukemia Chemo-Resistance in Hypoxic Microenvironment. Medical science monitor : international medical journal of experimental and clinical research 16 29400343
2016 Siah2 Protein Mediates Early Events in Commitment to an Adipogenic Pathway. The Journal of biological chemistry 16 27864366
2020 SIAH2 is Expressed in Adipocyte Precursor Cells and Interacts with EBF1 and ZFP521 to Promote Adipogenesis. Obesity (Silver Spring, Md.) 15 33155406
2023 CBX2-mediated suppression of SIAH2 triggers WNK1 accumulations to promote glycolysis in hepatocellular carcinoma. Experimental cell research 14 36780970
2022 Sinomenine Inhibits Vasculogenic Mimicry and Migration of Breast Cancer Side Population Cells via Regulating miR-340-5p/SIAH2 Axis. BioMed research international 14 35309179
2019 Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge. Biology of sex differences 14 30987673
1995 Expression of Siah-2, a vertebrate homologue of Drosophila sina, in germ cells of the mouse ovary and testis. Cell and tissue research 14 7895278
2022 SIAH2 regulates DNA end resection and replication fork recovery by promoting CtIP ubiquitination. Nucleic acids research 13 36155803
2016 The expression and function of E3 ligase SIAH2 in acute T lymphoblastic leukemia. Leukemia research 13 26859780
2013 A common variant in the SIAH2 locus is associated with estrogen receptor-positive breast cancer in the Chinese Han population. PloS one 13 24244489
2022 Siah2-GRP78 interaction regulates ROS and provides a proliferative advantage to Helicobacter pylori-infected gastric epithelial cancer cells. Cellular and molecular life sciences : CMLS 12 35816252
2014 Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells. The Journal of surgical research 12 24656476
2023 YTHDF1 enhances stemness and chemoresistance in triple-negative breast cancer cells by upregulating SIAH2. Molecular carcinogenesis 11 37983722
2022 SIAH2 regulates colorectal cancer tumorigenesis via PI3K/ATK signaling pathway. Tissue & cell 11 35926257
2021 Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation. Journal of biomedical science 11 33536006
2022 "The ubiquitin ligase SIAH2 is a female-specific regulator of circadian rhythms and metabolism". PLoS genetics 10 35789210
2014 Hypoximimetic activity of N-acyl-dopamines. N-arachidonoyl-dopamine stabilizes HIF-1α protein through a SIAH2-dependent pathway. Biochimica et biophysica acta 10 25090972
2013 The E3 ubiquitin ligase SIAH2 is a prosurvival factor overexpressed in oral cancer. Anticancer research 10 24222137
2022 Modulating the Siah2-PHD3-HIF1α axis and/or autophagy potentially retard colon cancer proliferation possibly, due to the damping of colon cancer stem cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 9 35994813
2021 Targeting ADT-Induced Activation of the E3 Ubiquitin Ligase Siah2 to Delay the Occurrence of Castration-Resistant Prostate Cancer. Frontiers in oncology 8 33937036
2016 Regulation of tumor suppressor EAF2 polyubiquitination by ELL1 and SIAH2 in prostate cancer cells. Oncotarget 7 27058417
2007 Isolation of Xenopus HIF-prolyl 4-hydroxylase and rescue of a small-eye phenotype caused by Siah2 over-expression. Biochemical and biophysical research communications 7 17303083
2013 Siah2-deficient mice show impaired skin wound repair. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 6 23627548
2011 Homology modeling and in silico screening of inhibitors for the substrate binding domain of human Siah2: implications for hypoxia-induced cancers. Journal of molecular modeling 6 21409570
2024 SIAH2 suppresses c-JUN pathway by promoting the polyubiquitination and degradation of HBx in hepatocellular carcinoma. Journal of cellular and molecular medicine 5 38842124
2024 SIAH2-Mediated Degradation of ACSL4 Inhibits the Anti-Tumor Activity of CD8+ T Cells in Hepatocellular Carcinoma. Critical reviews in eukaryotic gene expression 4 38842200
2023 Methods to Evaluate the Effects of HAT/KAT Inhibition on SIAH2-Driven Reactive Oxygen Species Generation in Helicobacter pylori-Infected Gastric Epithelial Cells. Methods in molecular biology (Clifton, N.J.) 4 36255634
2025 Siah2 antagonism of Pard3/JamC modulates Ntn1-Dcc signaling to regulate cerebellar granule neuron germinal zone exit. Nature communications 3 39774925
2025 The deacetylases HDAC1/HDAC2 control JAK2V617F-STAT signaling through the ubiquitin ligase SIAH2. Signal transduction and targeted therapy 3 40877230
2023 Siah2 inhibitor and the metabolic antagonist Oxamate retard colon cancer progression and downregulate PD1 expression. Recent patents on anti-cancer drug discovery 3 36650629
2020 The Ubiquitin Ligase SIAH2 Negatively Regulates Glucocorticoid Receptor Activity and Abundance. Biomedicines 3 33396678
2007 Regulation of repp86 stability by human Siah2. Biochemical and biophysical research communications 3 17716627
2025 SIAH2-AS1 stimulates breast cancer cell proliferation and migration via the Wnt/β-catenin signaling pathway. Scientific reports 2 40595045
2026 Siah2 is a lipid-mediated metabolic sensor in adipose tissue macrophage. Journal of lipid research 1 41690475
2025 The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance. Cell death & disease 1 39875361
2024 SIAH2 is specifically expressed during cervical carcinogenesis, and closely relates to the abnormal proliferation of cervical epithelial cells. Heliyon 1 38828323
2024 Antagonistic action of Siah2 and Pard3/JamC to promote germinal zone exit of differentiated cerebellar granule neurons by modulating Ntn1 signaling via Dcc. Research square 1 39399669
2026 CBX2 promotes cisplatin resistance in ovarian cancer via SIAH2-mediated β-catenin stabilization and ATG9B-dependent autophagy activation. Journal of ovarian research 0 41495834
2026 SIAH2-WNK1 Signaling Drives Glycolytic Metabolism and Therapeutic Resistance in Colorectal Cancer. International journal of molecular sciences 0 41596707
2026 SIAH2-EPHB6 axis enhances filopodia formation in hepatocellular carcinoma cells by regulating RHOF. Cell & bioscience 0 42036676
2024 Siah2- and LRSAM1-mediated K63-linked ubiquitination of snakehead vesiculovirus nucleoprotein facilitates viral replication. Journal of virology 0 38842318
2015 Loss of Siah2 does not impact angiogenic potential of murine endothelial cells. Microvascular research 0 26275748
2014 Commentary on "the E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity." Qi J, Tripathi M, Mishra R, Sahgal N, Fazli L, Ettinger S, Placzek WJ, Claps G, Chung LW, Bowtell D, Gleave M, Bhowmick N, Ronai ZA, Signal Transduction Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.: Cancer Cell 2013;23(6):332-46. Urologic oncology 0 24445292

Missed literature

Know a paper Affinage missed for SIAH2? Flag it for the maintainers and the community.

No submissions yet.