Affinage

SIAH2

E3 ubiquitin-protein ligase SIAH2 · UniProt O43255

Length
324 aa
Mass
34.6 kDa
Annotated
2026-04-28
96 papers in source corpus 54 papers cited in narrative 54 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIAH2 is a RING finger E3 ubiquitin ligase that functions as a central hypoxia-responsive degradation hub, targeting a remarkably broad substrate repertoire to control the HIF pathway, Hippo signaling, DNA damage response, mitochondrial dynamics, circadian rhythmicity, androgen receptor activity, immune cell function, and metabolic homeostasis. Under hypoxia, SIAH2 ubiquitinates prolyl hydroxylases PHD1/PHD3 for proteasomal degradation, thereby stabilizing HIF-1α; Siah1a/Siah2 double-null cells completely lack hypoxic HIF-1α induction, which is rescued by PHD3 knockdown (PMID:15210114). Beyond the hypoxic response, SIAH2 degrades LATS2 to activate YAP/Hippo signaling (PMID:25438054), AKAP121 to promote mitochondrial fission (PMID:22099302), CHK2 and CtIP to modulate the DNA damage response (PMID:26751770, PMID:36155803), RevErbα to regulate circadian period length (PMID:26392558), NRF1 to reprogram mitochondrial metabolism (PMID:30833558), p27 to control Treg proliferation and antitumor immunity (PMID:31911617), and NCOR1-bound androgen receptor to selectively activate AR target genes (PMID:23518348). SIAH2 activity is itself regulated by phosphorylation from multiple kinases (DYRK2, HIPK2, CHK2, Src, MRCK β, Plk3), by acetylation at K139, by stabilizing binding partners (AKR1C3, Ski, DHX15), and by the deubiquitinase USP13 which modulates SIAH2 autodegradation (PMID:22878263, PMID:19043406, PMID:21659512, PMID:22037769).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2002 High

    Establishing SIAH2 as a stress-responsive RING-dependent E3 ligase: SIAH2 was shown to ubiquitinate TRAF2 in a RING-domain-dependent manner under TNFα/stress conditions, promoting TRAF2 degradation and modulating JNK/NF-κB signaling and apoptosis, defining its catalytic mechanism and first physiological substrate.

    Evidence In vitro ubiquitylation with RING-mutant control, Siah2−/− MEFs showing prolonged TRAF2 half-life

    PMID:12411493

    Open questions at the time
    • Structural basis for RING-domain E2 selectivity not determined
    • Whether TRAF2 is a direct or scaffold-mediated substrate was not resolved
  2. 2003 High

    Defining in vivo requirements: Siah2 knockout mice revealed myeloid progenitor expansion, and Siah1a/Siah2 double knockouts demonstrated embryonic/neonatal lethality, establishing partially overlapping essential functions between paralogs.

    Evidence Siah2−/− and Siah1a/Siah2 double-KO mice, bone marrow colony assays

    PMID:14645526

    Open questions at the time
    • Specific substrates responsible for myeloid expansion not identified
    • Molecular basis for paralog functional overlap not defined
  3. 2004 High

    Identifying SIAH2 as the master regulator of the HIF-1α hypoxic response: SIAH2 was shown to target PHD1 and PHD3 for proteasomal degradation under hypoxia, with Siah1a/2 double-null cells completely lacking HIF-1α induction—rescued by PHD3 knockdown—placing SIAH2 upstream of the entire oxygen-sensing pathway.

    Evidence Siah2−/− and Siah1a/2 double-null MEFs, RNAi rescue, in vivo hypoxia in Siah2-null mice

    PMID:15210114

    Open questions at the time
    • Mechanism by which hypoxia increases SIAH2 activity toward PHDs not fully delineated
    • Relative contributions of Siah1 vs Siah2 to PHD degradation in different tissues unresolved
  4. 2007 High

    Structural determinants of PHD substrate selectivity were mapped: PHD3 lacks the N-terminal domain that protects PHD1/PHD2 from SIAH2-mediated degradation, and SIAH2 preferentially degrades the more catalytically active low-MW PHD3 complex, explaining selective pathway control.

    Evidence Deletion mutagenesis, biochemical fractionation, in vitro hydroxylation assay

    PMID:16958618

    Open questions at the time
    • Crystal structure of SIAH2–PHD3 complex not solved
    • Whether similar N-terminal protection mechanisms apply to non-PHD substrates unknown
  5. 2008 High

    SIAH2 was established as both phosphorylation-regulated and a regulator of its own kinases: HIPK2 phosphorylates SIAH2 under normoxia to weaken binding, while under hypoxia enhanced interaction leads to HIPK2 degradation, revealing a reciprocal regulatory switch that modulates hypoxia-inducible gene expression.

    Evidence Phosphosite mapping, co-IP, Siah2-deficient cells, ubiquitylation assay

    PMID:19043406

    Open questions at the time
    • Phosphatase(s) that dephosphorylate SIAH2 under hypoxia not identified
    • Dynamics of HIPK2-SIAH2 switch in tissues in vivo not characterized
  6. 2008 High

    SIAH2 was shown to drive tumorigenesis through both HIF-dependent (PHD3 degradation) and HIF-independent (Sprouty2/Ras) mechanisms, establishing it as a multi-pathway oncogenic hub in melanoma metastasis.

    Evidence Dominant-negative RING mutant and competitive peptide approaches in syngeneic mouse melanoma model

    PMID:18946040

    Open questions at the time
    • Full catalog of HIF-independent SIAH2 substrates in melanoma not determined
    • Therapeutic window of SIAH2 inhibition in vivo not established
  7. 2011 High

    SIAH2's substrate repertoire expanded to mitochondrial dynamics and telomere maintenance: SIAH2 degrades AKAP121 to relieve PKA-dependent Drp1 inhibition (promoting mitochondrial fission and cardiomyocyte apoptosis) and ubiquitinates TIN2 to disrupt shelterin complex assembly at telomeres.

    Evidence Siah2−/− cells/mice with myocardial infarction model for AKAP121; reconstituted in vitro ubiquitylation with purified proteins for TIN2

    PMID:22064479 PMID:22099302

    Open questions at the time
    • Whether SIAH2-TIN2 axis affects telomere length in vivo not tested
    • Full scope of SIAH2 targets at mitochondria not catalogued
  8. 2011 High

    SIAH2 autodegradation was shown to be regulated by the deubiquitinase USP13 through a non-catalytic ubiquitin-binding mechanism, and by Src phosphorylation which activates SIAH2 toward C/EBPδ in breast cancer, establishing upstream regulatory inputs.

    Evidence USP13 ubiquitin-binding domain mutants and catalytic site mutants; in vitro Src phosphorylation of SIAH2 with C/EBPδ co-IP and degradation assays

    PMID:21659512 PMID:22037769

    Open questions at the time
    • USP13 binding site on SIAH2 not structurally defined
    • Additional post-translational modifications of SIAH2 beyond phosphorylation not systematically surveyed at this point
  9. 2012 High

    SIAH2 was placed in androgen receptor signaling: it selectively degrades NCOR1-bound inactive AR, promoting expression of AR target genes involved in lipid metabolism and proliferation, and is required for prostate cancer growth under androgen deprivation.

    Evidence Co-IP of SIAH2–NCOR1–AR complex, ubiquitination assay, castration mouse model

    PMID:23518348

    Open questions at the time
    • Whether SIAH2 targets other nuclear receptor corepressor complexes not tested
    • Mechanism by which SIAH2 distinguishes NCOR1-bound from active AR not defined
  10. 2012 High

    DYRK2 was identified as a SIAH2 kinase that phosphorylates five sites to enhance SIAH2 activity and alter its subcellular localization, while SIAH2 reciprocally degrades DYRK2—establishing a second reciprocal kinase-E3 ligase feedback loop.

    Evidence Phosphosite mapping, phosphomimetic/mutant constructs, subcellular fractionation, PHD3 degradation readout

    PMID:22878263

    Open questions at the time
    • Net effect of DYRK2-SIAH2 loop on HIF signaling dynamics not modeled
    • Whether other DYRK family members similarly regulate SIAH2 not tested
  11. 2014 High

    SIAH2 was connected to Hippo signaling and metabolic reprogramming: it degrades LATS2 under hypoxia to activate YAP, and degrades the OGDH2 splice variant to suppress α-ketoglutarate dehydrogenase activity and redirect glutamine metabolism.

    Evidence LATS2 rescue experiments with xenograft model; OGDH2 K336A ubiquitination-site mutant with metabolic flux analysis

    PMID:24506869 PMID:25438054

    Open questions at the time
    • Whether SIAH2-LATS2 axis is active in non-hypoxic contexts not clear
    • Contribution of OGDH2 degradation relative to other TCA cycle changes under hypoxia not quantified
  12. 2015 Medium

    SIAH2 was linked to circadian clock regulation by targeting RevErbα for proteasomal degradation; SIAH2 depletion stabilizes RevErbα and lengthens circadian period, establishing SIAH2 as a circadian regulator.

    Evidence Functional E3 ligase screen, siRNA depletion, RevErbα stability and circadian period measurement

    PMID:26392558

    Open questions at the time
    • Whether SIAH2 itself oscillates with circadian rhythm not demonstrated
    • Direct ubiquitination site on RevErbα not mapped
  13. 2016 High

    Zyxin was identified as a scaffold that forms a ternary complex with SIAH2 and LATS2 under hypoxia and TGF-β, facilitating LATS2 ubiquitination—providing the first adaptor-dependent mechanism for SIAH2 substrate targeting.

    Evidence Ternary complex co-IP, zyxin siRNA epistasis, ubiquitination assay

    PMID:27030211

    Open questions at the time
    • Whether other scaffold proteins similarly direct SIAH2 to substrates not systematically explored
    • Structural basis of ternary complex not determined
  14. 2019 High

    SIAH2 was shown to ubiquitinate NRF1 at K230, downregulating nuclear-encoded mitochondrial genes and reprogramming metabolism toward the Warburg effect while promoting pro-tumorigenic macrophage polarization—linking SIAH2 to immunometabolic regulation.

    Evidence K230 ubiquitination site identification, SIAH2 knockdown/overexpression, mitochondrial gene expression and macrophage polarization assays

    PMID:30833558

    Open questions at the time
    • Whether NRF1 degradation by SIAH2 is tissue-specific not addressed
    • Downstream immune consequences in tumor microenvironment not fully characterized
  15. 2020 High

    SIAH2 was established as a regulator of antitumor immunity: by degrading p27 in Tregs, SIAH2 promotes Treg proliferation and tumor infiltration; Siah2-knockout mice show Treg G1 arrest and synergy with anti-PD-1 immunotherapy.

    Evidence Siah2−/− mice, Treg cell cycle flow cytometry, p27 protein analysis, anti-PD-1 combination in vivo

    PMID:31911617

    Open questions at the time
    • Whether SIAH2 affects other immune cell subsets in the tumor microenvironment not comprehensively evaluated
    • Mechanism of selective p27 targeting in Tregs versus other T cell subsets not defined
  16. 2022 High

    SIAH2 was shown to regulate homologous recombination repair through non-degradative ubiquitination of CtIP at N-terminal lysines, required for CtIP recruitment to DSBs and stalled replication forks, DNA end resection, and fork recovery—expanding SIAH2 beyond degradative ubiquitination.

    Evidence CtIP lysine mutants, DSB end resection assay, HR repair assay, replication fork recovery assay

    PMID:36155803

    Open questions at the time
    • Ubiquitin chain type on CtIP (K63 vs. monoubiquitin) not fully characterized
    • Whether SIAH2-CtIP axis is regulated by hypoxia not addressed
  17. 2022 High

    SIAH2 was identified as a female-specific regulator of circadian liver metabolism: Siah2-deficient female mice show dramatic remodeling of rhythmic transcriptome, disrupted lipid/lipoprotein patterns, and increased adiposity—effects absent in males.

    Evidence Siah2−/− male and female mice, liver RNA-seq rhythmic analysis, metabolic and lipid profiling

    PMID:35789210

    Open questions at the time
    • Molecular basis for sex-specific SIAH2 circadian function not determined
    • Whether estrogen receptor signaling intersects with SIAH2 not tested
  18. 2025 High

    SIAH2's substrate scope expanded to include JAK2V617F via a surface-exposed degron motif (VLP1002), partnering with E2 enzyme UBCH8 for K48-linked degradation—identifying SIAH2 as a mechanism of HDAC inhibitor efficacy in myeloproliferative neoplasms.

    Evidence HDAC1/2 KO, UBCH8 co-IP, degron motif mapping, JAK2V617F degradation assay, SIAH2-KO MPN cells

    PMID:40877230

    Open questions at the time
    • Whether SIAH2 degrades wild-type JAK2 with comparable efficiency not tested
    • Whether SIAH2-dependent JAK2V617F degradation operates in patient-derived cells in vivo not confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive substrate cataloging, no high-resolution structure of SIAH2 in complex with any substrate or E2 enzyme exists, and the mechanism by which hypoxia activates SIAH2 catalytic function (beyond kinase inputs) remains undefined; the basis for sex-specific circadian regulation and the full scope of non-degradative ubiquitination events are open questions.
  • No crystal or cryo-EM structure of SIAH2 with substrate or E2
  • Mechanism of hypoxia-induced SIAH2 activation beyond phosphorylation unknown
  • Systematic identification of non-degradative SIAH2 ubiquitination events needed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 14
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 9 R-HSA-8953897 Cellular responses to stimuli 6 R-HSA-162582 Signal Transduction 5 R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 R-HSA-9909396 Circadian clock 2
Partners
AKAP121DHX15DYRK2HIPK2LATS2PHD3UBCH8USP13

Evidence

Reading pass · 54 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Siah2 is an E3 ubiquitin ligase that targets PHD1 and PHD3 (prolyl hydroxylases) for proteasome-dependent degradation under hypoxia, thereby controlling HIF-1α abundance. Siah2-null fibroblasts show prolonged PHD3 half-life and lower HIF-1α levels during hypoxia; HIF-1α expression is completely inhibited in Siah1a/2 double-null cells and rescued by PHD3 RNAi knockdown. Genetic knockout (Siah2-/- and Siah1a/2 double-null MEFs), RNAi rescue, protein half-life assays, in vivo hypoxia model (Siah2 null mice) Cell High 15210114
2002 Siah2 targets TRAF2 for ubiquitylation and proteasomal degradation under stress conditions (TNF-α and actinomycin D treatment). Wild-type but not RING-mutant Siah2 mediates this ubiquitylation in vitro, and TRAF2 half-life is prolonged in Siah2-/- MEFs subjected to stress. This reduces JNK activity and NF-κB transcriptional activation, and Siah2-mediated TRAF2 degradation promotes apoptosis. In vitro ubiquitylation assay, Siah2-/- MEFs, RING-domain mutant Siah2, protein half-life measurement The EMBO journal High 12411493
2003 Genetic analysis of Siah2 knockout mice reveals expansion of myeloid progenitor cells in bone marrow and increased osteoclast production in vitro. Combined Siah1a/Siah2 double knockout causes embryonic/neonatal lethality, demonstrating partially overlapping in vivo functions. Knockout mouse generation and phenotypic analysis, bone marrow colony assays Molecular and cellular biology High 14645526
2007 PHD3 lacks the N-terminal extension present in PHD1 and PHD2; deletion of this domain from PHD1/PHD2 renders them susceptible to Siah2-mediated degradation. PHD3 forms homo- and hetero-multimers; the lower-molecular-mass PHD3 complex shows higher HIF-1α hydroxylation activity and co-localizes with Siah2, indicating Siah2 preferentially degrades the more catalytically active form of PHD3. Biochemical fractionation, co-localization, deletion mutagenesis, in vitro hydroxylation assay The Biochemical journal High 16958618
2008 Under normoxia, HIPK2 phosphorylates Siah2 at positions Ser26, Ser28, and Ser68, weakening their mutual binding and destabilizing HIPK2. Under hypoxia, HIPK2/Siah2 interaction markedly increases, resulting in efficient polyubiquitylation and proteasomal degradation of HIPK2. Hypoxia-induced HIPK2 elimination is markedly reduced in Siah2-deficient cells, relieving repression of hypoxia-inducible genes. Co-immunoprecipitation, Siah2-deficient cells, phosphorylation mapping, ubiquitylation assay Nature cell biology High 19043406
2008 Siah2 regulates melanoma tumorigenesis and metastasis through both HIF-dependent (via PHD3 degradation and HIF-1α stabilization) and HIF-independent mechanisms (via Sprouty2 degradation, a negative regulator of Ras signaling). A peptide that outcompetes Siah2-interacting proteins reduces metastasis via HIF-1α, while a dominant-negative Siah2 RING mutant reduces tumorigenesis via Sprouty2. Dominant-negative Siah2 RING mutant expression, competitive peptide, syngeneic mouse melanoma model Proceedings of the National Academy of Sciences of the United States of America High 18946040
2009 Menadione (vitamin K3) is identified as a specific inhibitor of Siah2 ubiquitin ligase activity. It attenuates Siah2 self-ubiquitination and increases expression of Siah2 substrates PHD3 and Sprouty2, with concomitant decreases in HIF-1α and pERK. Effects are absent in Siah2-KO cells, confirming Siah-dependence. The inhibition is ROS-independent. High-throughput electro-chemiluminescent ubiquitin ligase activity assay, Siah-KO cells as specificity control, xenograft tumor model Pigment cell & melanoma research High 19712206
2010 Siah2-dependent HIF-1α availability cooperates with FoxA2 transcription factor to recruit p300 and transactivate select HIF-regulated genes (Hes6, Sox9, Jmjd1a) required for neuroendocrine prostate tumor formation. Formation of NE prostate tumors in TRAMP mice is suppressed in Siah2-null mice. Siah2 knockout in TRAMP mouse model, transcriptional co-activation assay, p300 recruitment, gene expression analysis Cancer cell High 20609350
2011 Hypoxia-induced mitochondrial fission depends on Siah2-mediated ubiquitination and degradation of the mitochondrial scaffold protein AKAP121. Loss of AKAP121 relieves PKA-dependent inhibitory phosphorylation of Drp1 and increases Drp1-Fis1 interaction, promoting fission. High AKAP121 levels in Siah2-/- cells attenuate fission and reduce cardiomyocyte apoptosis; Siah2-/- mice show reduced infarct size after myocardial infarction. Siah2-/- cells and mice, subcellular fractionation, PKA phosphorylation assay, Drp1-Fis1 co-IP, myocardial infarction model Molecular cell High 22099302
2011 USP13 deubiquitinase regulates Siah2 stability by attenuating its autodegradation via noncatalytic ubiquitin-binding domains (not isopeptidase activity). USP13 overexpression stabilizes Siah2 but attenuates its ability to target PHD3 and Sprouty2 for degradation; USP13 knockdown decreases stability of both Siah2 and Sprouty2. Under hypoxia, USP13 expression is attenuated, relieving Siah2 inhibition. USP13 overexpression/shRNA, ubiquitin-binding domain mutants, catalytic site mutants, substrate degradation assays The Journal of biological chemistry High 21659512
2011 Src tyrosine kinase phosphorylates SIAH2, activating it; activated SIAH2 interacts with C/EBPδ (but not C/EBPβ) and promotes its polyubiquitination and proteasomal degradation. This pathway supports cyclin D1 levels, Rb phosphorylation, cell motility, invasiveness, and survival of transformed breast tumor cells. In vitro Src phosphorylation of SIAH2, co-IP of SIAH2-C/EBPδ, ubiquitination assay, degradation-resistant C/EBPδ mutants, SKI-606 pharmacological inhibition Molecular and cellular biology High 22037769
2011 Siah2 acts as E3 ligase to directly ubiquitylate TIN2 (a central shelterin subunit) in vitro using purified proteins. TIN2 binds Siah2 in vivo; Siah2 depletion stabilizes TIN2. Siah2 overexpression causes loss of TIN2 at telomeres in a RING-domain-dependent manner, resulting in loss of TPP1 but not TRF1/TRF2 from telomeres. Purified protein in vitro ubiquitylation assay, co-IP, RNAi depletion, telomere ChIP/immunofluorescence Molecular and cellular biology High 22064479
2011 Siah2 is identified as an E3 ubiquitin ligase that mediates proteasomal degradation of HDAC3. The Ski protein interacts with Siah2 and, by inhibiting Siah2 E3 ubiquitin ligase activity (evidenced by Siah2 self-stabilization upon Ski co-expression), stabilizes HDAC3. Only Ski truncation mutants that form a complex with Siah2 can stabilize HDAC3. Co-immunoprecipitation, Ski truncation mutant analysis, co-expression degradation assay Biochemical and biophysical research communications Medium 20691163
2012 Siah2 targets NCOR1-bound, transcriptionally-inactive androgen receptor (AR) for ubiquitin-dependent degradation, thereby selectively promoting expression of AR target genes involved in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation in vitro and in vivo. Co-IP of Siah2-NCOR1-AR complex, ubiquitination assay, Siah2 knockdown/overexpression, castration mouse model Cancer cell High 23518348
2012 DYRK2 serine/threonine kinase phosphorylates SIAH2 at five residues (Ser16, Thr26, Ser28, Ser68, Thr119). Phosphomimetic vs. phospho-mutant SIAH2 show different subcellular localizations and altered PHD3-degrading activity; phosphorylated SIAH2 is more active. Reciprocally, SIAH2 facilitates DYRK2 polyubiquitination and proteasomal degradation, which is enhanced under hypoxia. Phosphosite mapping, phosphomimetic/phospho-mutant SIAH2 constructs, subcellular fractionation, PHD3 degradation assay, mutual ubiquitination assay Journal of molecular cell biology High 22878263
2012 Siah2 ubiquitin ligase activity controls ASPP2 availability under hypoxia. LC-MS/MS identified ASPP2 and ASPP1 as Siah2-interacting proteins; degron motifs within ASPP2 required for Siah2-mediated ubiquitination and proteasomal degradation were mapped. Siah2 inhibition increases ASPP2 levels, enhancing tight junction integrity and polarized architecture in 3D organotypic culture. LC-MS/MS interactome, co-IP, degron motif mutagenesis, ubiquitination assay, 3D organotypic culture Oncogene High 23644657
2012 Siah2 ubiquitin ligase activity controls the stability of PPARγ by promoting its ubiquitylation. Siah2 expression is upregulated during adipogenesis, PPARγ interacts with Siah2 during this process, and Siah2 is required for adipogenesis in 3T3-L1 cells. RNAi screen, co-IP, ubiquitylation assay, Siah2 KO adipogenesis model Endocrinology Medium 22294748
2013 Siah2 interacts with Nrf2 through a binding motif and promotes its proteasomal degradation under hypoxia independently of Keap1. Siah2 knockdown prevents hypoxic Nrf2 suppression and attenuates ubiquitination of an Nrf2 mutant lacking Keap1-binding domain, indicating direct Siah2-Nrf2 interaction. Co-IP, siRNA knockdown, hypoxia treatment, ubiquitination assay The Journal of biological chemistry Medium 23645672
2013 SIAH2 interacts with HDAC3 and promotes its polyubiquitination and proteasomal degradation. miR-335 targets SIAH2 mRNA, reducing SIAH2 levels and thereby increasing HDAC3 expression. Co-IP, ubiquitination assay, miRNA target validation Molecules and cells Medium 25997740
2014 HIF-1 activation promotes SIAH2-targeted ubiquitination and proteolysis of OGDH2 (the 48 kDa splice variant of the E1 subunit of the α-ketoglutarate dehydrogenase complex). Mutation of the ubiquitinated lysine residue (K336A) on OGDH2 reverses the hypoxic drop in αKGDH activity and stimulates glutamine oxidation, establishing the SIAH2-OGDH2 axis as a regulator of metabolic reprogramming. siRNA knockdown of SIAH2, K336A lysine mutant OGDH2, enzymatic activity assay, metabolic flux analysis Cell metabolism High 24506869
2014 SIAH2 destabilizes LATS2, a critical Hippo pathway kinase, via ubiquitin-mediated proteasomal degradation in response to hypoxia, leading to YAP activation. Loss of SIAH2 suppresses tumorigenesis in a LATS2-dependent manner in xenograft models. Co-IP, ubiquitination assay, SIAH2 knockdown/knockout, LATS2 rescue, xenograft mouse model Nature cell biology High 25438054
2014 SIAH2 promotes proteasomal degradation of TYK2, suppressing TYK2-STAT3 signaling in lung cancer cells. p53 activation induces SIAH2, which depletes TYK2 and abrogates STAT1/STAT3 tyrosine phosphorylation. Co-IP, siRNA knockdown, ubiquitination assay, STAT3 phosphorylation readout Oncotarget Medium 24833526
2015 Siah2 regulates the stability of RevErbα (Nr1d1), a core circadian clock component, promoting its proteasomal degradation. Siah2 overexpression destabilizes RevErbα/β; siRNA depletion of Siah2 stabilizes endogenous RevErbα and delays its circadian degradation, lengthening circadian period. Cell-based E3 ligase functional screen, siRNA depletion, RevErbα stability assay, 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 its self-ubiquitination and autodegradation, thereby increasing Siah2 protein levels. This creates a positive feedback: Siah2 promotes AKR1C3 expression, which in turn stabilizes Siah2. Co-IP, self-ubiquitination assay, Siah2 KD, re-expression of catalytically inactive AKR1C3 The Journal of biological chemistry Medium 26160177
2016 SIAH2 interacts with and mediates ubiquitination and proteasomal degradation of CHK2. CHK2 degradation is independent of its activation or kinase activity. CHK2 phosphorylates SIAH2 at Thr26, Ser28, and Thr119, modifying Siah2 substrate-targeting ability. DNA damage disrupts the SIAH2-CHK2 interaction, stabilizing CHK2. Hypoxia-induced SIAH2 activity decreases CHK2 levels, impairing DNA damage response. Co-IP, ubiquitination assay, SIAH2-deficient cells, CHK2 kinase-dead mutant, phospho-site mapping Oncogene High 26751770
2016 Zyxin (a LIM domain protein) acts as a scaffold protein that forms a ternary complex with Lats2 and Siah2 in response to hypoxia and TGF-β, stabilizing their interaction and facilitating Lats2 ubiquitination and degradation, leading to YAP dephosphorylation and activation. Co-IP of ternary complex, ubiquitination assay, Zyxin siRNA knockdown, migration/proliferation assays Nature communications High 27030211
2016 SIAH2 acts as an E3 ligase for EAF2 polyubiquitination. Co-IP detects EAF2 binding to SIAH2, and SIAH2 overexpression enhances EAF2 polyubiquitination. ELL1 (EAF2's binding partner) blocks EAF2 ubiquitination by SIAH2, stabilizing EAF2. Co-IP, ubiquitination assay, ELL1 co-transfection competition assay Oncotarget Medium 27058417
2017 DHX15 RNA helicase forms a complex with AR and Siah2 through AR's nuclear export signal (NESAR); DHX15 stabilizes Siah2 and enhances its E3 ubiquitin ligase activity for AR, resulting in AR activation. This is independent of DHX15's ATPase activity. Yeast mutagenesis screen, co-IP, E3 ligase activity assay, DHX15 ATPase-dead mutant, xenograft tumor model Oncogene High 28991234
2017 SIAH2 binds to Plk3 (polo-like kinase 3) through Plk3's polo-box domain and mediates its ubiquitination and proteasomal degradation under hypoxia or nickel exposure. Plk3 reciprocally suppresses SIAH2 protein level in a kinase-activity-dependent manner, forming a mutual regulatory network controlling the hypoxic response. Co-IP, ubiquitination assay, polo-box domain mutant, kinase-active/inactive Plk3 constructs, protein half-life assay The Journal of biological chemistry High 28515325
2018 Testin (TES) and filamin-C (FLN-C) interact with Siah2 and undergo proteasomal degradation. This degradation is potentiated by Siah2 acetylation at Lys139 (K139) in H. pylori-infected gastric cancer cells. Acetylated Siah2 (ac-K139) disrupts filopodia and promotes lamellipodia formation, enhancing invasiveness and migration. Co-IP, acetylation-site mutagenesis (K139), ubiquitination/degradation assay, invasion/migration assays The international journal of biochemistry & cell biology Medium 30063986
2018 PIWIL2 interacts with HDAC3 and competitively blocks Siah2-mediated HDAC3 ubiquitination and degradation by competing for Siah2 binding. PIWIL2 also facilitates CK2α-mediated HDAC3 phosphorylation, enhancing HDAC3 activity. Co-IP, competitive ubiquitination assay, HDAC3 activity assay Cell death & disease Medium 29555935
2019 SIAH2 ubiquitinates and degrades NRF1 (Nuclear Respiratory Factor 1) on lysine 230, downregulating nuclear-encoded mitochondrial gene expression (including pyruvate dehydrogenase beta) and causing metabolic reprogramming (enhanced Warburg effect) and pro-tumor immune response. Ubiquitination assay identifying K230 on NRF1, SIAH2 knockdown/overexpression, mitochondrial gene expression analysis, macrophage polarization assay Nature communications High 30833558
2019 Siah2 proteasomally degrades Lats1/2 in a monocrotaline-induced pulmonary arterial hypertension rat model, leading to YAP dephosphorylation and nuclear localization, promoting pulmonary arterial smooth muscle cell proliferation. Siah2 inhibition (via vitamin K3 or MG-132) prevents Lats1/2 degradation and attenuates pulmonary arterial remodeling. Western blot for Siah2/Lats1/2/YAP, proteasome activity assay, YAP subcellular localization, Siah2 inhibitor (vitamin K3) treatment in vivo Life sciences Medium 31837334
2020 Siah2 regulates Treg cell cycle progression by targeting p27 (cyclin-dependent kinase inhibitor) for degradation. In Siah2-/- mice, tumor-infiltrated Tregs exhibit G1 arrest with elevated p27 levels. Loss of Siah2 reduces Treg proliferation and tumor infiltration, inhibiting melanoma growth and synergizing with anti-PD-1 therapy. Siah2-/- mouse model, flow cytometry of Treg cell cycle/proliferation, p27 protein level analysis, anti-PD-1 combination in vivo Nature communications High 31911617
2020 Siah2 interacts with and degrades HO-1 (heme oxygenase-1) in a RING domain-dependent manner. SIAH2 knockout mice show elevated HO-1 protein levels in heart, kidney, and skeletal muscle. SIAH2-deficient cells also show reduced GPX4 expression, rendering them more sensitive to ferroptosis. Siah2 KO mice (organ-specific analysis), RING-domain-dependent degradation assay, co-IP Scientific reports Medium 32042051
2020 Siah2 interacts with NCX3 (Na+/Ca2+ exchanger isoform 3) at the mitochondria and promotes its degradation during hypoxia. In Siah2-KO neurons, NCX3 degradation is prevented, preserving mitochondrial membrane potential, calcium homeostasis, oxidative capacity, and ATP production during oxygen-glucose deprivation. Co-immunoprecipitation, Siah2-KO neurons, mitochondrial function assays (ΔΨm, [Ca2+]m, ATP), confocal microscopy Cell communication and signaling Medium 32164721
2020 In cerebellar granule neuron progenitors, Siah2 expression is maintained by Shh signaling through a Ras/Mapk-dependent mechanism. Siah2 restrains primary cilium disassembly in a feed-forward fashion. Laminin in the germinal zone microenvironment signals through integrin β1 receptors to engage Ras/Mapk and cooperate with Shh to promote GNP ciliogenesis. Shh signaling pathway manipulation, Ras/Mapk inhibition, integrin β1 receptor perturbation, cilia length measurement Nature communications Medium 33082319
2021 MRCKβ kinase phosphorylates Siah2 at Ser6 and Thr279. Phospho-Siah2 (S6, T279) is more stable and tumorigenic than non-phosphorylated Siah2. Siah2 ubiquitinates and degrades MRCKβ, creating a mutual regulatory loop. Phosphorylation-null mutants (S6A, T279A) show abated tumorigenicity. Co-IP followed by mass spectrometry to identify kinase, phospho-site mutagenesis (S6A, T279A), ubiquitination assay, clonogenicity/invasion assays Journal of biomedical science Medium 33536006
2020 SIAH2 is expressed in adipocyte precursor cells (PDGFRα+ and SCA1+). In early adipogenesis, SIAH2 forms a protein complex with EBF1 and ZFP521 to enhance ubiquitylation and degradation of the antiadipogenic ZFP521 while increasing EBF1 protein levels. Co-IP of ternary SIAH2-EBF1-ZFP521 complex, ubiquitylation assay, primary adipocyte precursor cells from WT and SIAH2-null mice Obesity Medium 33155406
2022 SIAH2 interacts with CtIP and ubiquitinates it at N-terminal lysine residues, which is required for CtIP recruitment to DSBs and stalled replication forks, DNA end resection, homologous recombination repair, and recovery of stalled replication forks. Depleting SIAH2 or mutating key CtIP lysine residues impairs these functions. Co-IP, ubiquitination assay, CtIP lysine mutants, DSB end resection assay, HR repair assay, replication fork recovery assay Nucleic acids research High 36155803
2022 SIAH2 ubiquitinates and degrades DBC1 under hypoxia; OTUD5 deubiquitinase opposes this. Hypoxia promotes DBC1-SIAH2 interaction (over DBC1-OTUD5), resulting in DBC1 ubiquitination and proteasomal degradation, driving breast cancer progression. Co-IP, ubiquitination assay, SIAH2 knockout, OTUD5 rescue, SIAH2/DBC1 double KO eLife High 35913115
2022 Siah2 phosphorylation at S6 by H. pylori enhances proteasomal degradation of GRP78 (an antioxidant ER chaperone), potentiating ROS generation and mitochondrial damage in infected gastric epithelial cancer cells. P-S6-Siah2 also promotes aggresome accumulation and suppresses autophagosome formation. Phospho-specific Siah2 constructs (S6A phospho-null), co-IP with GRP78, ROS measurement, mitochondrial membrane potential assay Cellular and molecular life sciences Medium 35816252
2024 SIAH2 interacts with HBx (hepatitis B virus X protein) and induces K48-linked polyubiquitination and proteasomal degradation of HBx, dependent on SIAH2's E3 ligase activity. This inhibits HBx-associated HCC cell proliferation. Co-IP, K48-linkage-specific ubiquitination assay, E3 ligase activity-deficient SIAH2 mutant Journal of cellular and molecular medicine Medium 38842124
2024 SIAH2 induces K48-linked polyubiquitination and degradation of EPHB6, promoting filopodia formation and invasion/migration of HCC cells via RHOF modulation. Co-IP, K48-specific ubiquitination assay, SIAH2 overexpression/knockdown, filopodia quantification Cell & bioscience Medium 42036676
2023 SIAH2 interacts with WNK1 and mediates its ubiquitination and proteasomal degradation. In HCC, low SIAH2 (driven by CBX2/EZH2-mediated H3K27me3 on the SIAH2 promoter) leads to WNK1 accumulation, driving glycolysis and HCC proliferation. Co-IP of SIAH2-WNK1, ubiquitination assay, CBX2/EZH2 ChIP for H3K27me3, in vitro/in vivo proliferation assays Experimental cell research Medium 36780970
2025 SIAH2 ubiquitin ligase inhibits Dcc (Deleted in Colorectal Cancer) receptor surface recruitment by antagonizing Pard3/JamC-mediated promotion of Dcc surface localization, gating differentiation-linked repulsion to germinal zone Netrin-1 and regulating cerebellar granule neuron germinal zone exit. Genetic epistasis (Pard3, JamC, Siah2 perturbations), Dcc surface localization assay, neuronal differentiation readout Nature communications Medium 39774925
2025 HDAC1/HDAC2 control SIAH2 protein stability through acetylation. SIAH2, in conjunction with the E2 ubiquitin-conjugating enzyme UBCH8, mediates proteasomal degradation of JAK2V617F by binding its surface-exposed SIAH degron motif VLP1002 in the catalytic domain. SIAH2 KO reduces sensitivity of MPN cells to HDAC inhibitors. HDAC1/HDAC2 genetic knockout, UBCH8 co-IP, SIAH2 degron motif identification, JAK2V617F degradation assay, SIAH2-KO MPN cells Signal transduction and targeted therapy High 40877230
2024 SIAH2 mediates ubiquitination of ACSL4, inhibiting its expression. SIAH2 knockdown promotes CD8+ T cell-mediated ferroptosis of HCC cells via ACSL4 stabilization. Ubiquitination assay, co-IP, SIAH2 knockdown, CD8+ T cell flow cytometry, xenograft model Critical reviews in eukaryotic gene expression Low 38842200
2009 Siah2 interacts with MYPT1 (myosin phosphatase target subunit 1) through its substrate binding domain (aa 116-324) and a degenerate Siah-binding motif RLAYVAP (aa 493-499) within MYPT1, mediating proteasomal degradation of MYPT1 in neurons and glia. Co-IP, domain mapping (truncation mutants), Siah-binding motif identification, proteasomal degradation assay in neurons/glia Experimental cell research Medium 19744480
2007 In Xenopus embryos, overexpression of xSiah2 decreases PHD45 (PHD2 ortholog) but not PHD28 (PHD3 ortholog) protein levels, causing a small-eye phenotype; additional overexpression of PHD47 rescues this abnormality, establishing in vivo functional conservation of the Siah2-PHD regulatory axis. Xenopus overexpression, PHD protein level measurement, rescue experiment Biochemical and biophysical research communications Medium 17303083
2011 Siah2 interacts with PML-RARα (leukemia fusion protein) along with the E2 ubiquitin conjugase UBCH8 to mediate its proteasomal degradation. Co-IP of SIAH1/2-UBCH8-PML-RARα, protein stability assay The international journal of biochemistry & cell biology Medium 22037423
2016 Siah2 acts upstream of BMP-4 in adipogenesis, regulating factors including Wnt pathway genes, β-catenin, Zfp432, and Bmp-4. Loss of Siah2 is associated with sustained β-catenin expression post-induction. Siah2 overexpression in non-precursor fibroblasts promotes adipogenesis, while Siah2 shRNA in 3T3-L1 preadipocytes impairs it. Siah2 shRNA stable cells, Siah2-/- adipose tissue, BMP-4 rescue, β-catenin depletion epistasis The Journal of biological chemistry Medium 27864366
2022 SIAH2 is a female-specific regulator of circadian clock gene expression and liver metabolic rhythms. In Siah2-deficient female mice, expression of core circadian clock genes is altered, rhythmic transcriptome is dramatically remodeled (day-time genes increased, nighttime expression flipped), and daily lipid/lipoprotein patterns are disrupted, causing increased adiposity and impaired metabolic homeostasis—effects not observed in males. Siah2-/- mice (male and female), liver RNA-seq rhythmic analysis, metabolic phenotyping, lipid/lipoprotein profiling PLoS genetics High 35789210
2026 SIAH2 functions as a lipid-stimulated stress response protein in adipose tissue macrophages (ATMs). Macrophage-specific SIAH2 deletion increases glucose intolerance, insulin resistance, and ATM lipid accumulation in high-fat-fed male mice, associated with increased Cd36, Trem2, Tyrobp, and Hilpda1 expression. Proinflammatory lipids stimulate Siah2 mRNA in macrophages, and Siah2 suppresses PPARγ target genes in lipid metabolism. Macrophage-specific SIAH2 conditional KO mice, glucose/insulin tolerance testing, ATM lipid accumulation, gene expression analysis Journal of lipid research Medium 41690475

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 355 15210114
2014 Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell metabolism 302 24506869
2014 Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Nature cell biology 214 25438054
2011 Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. Molecular cell 211 22099302
2010 Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer cell 202 20609350
2013 The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity. Cancer cell 139 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 107 12411493
2016 Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways. Nature communications 86 27030211
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 86 18946040
2019 The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression. Nature communications 67 30833558
2009 Inhibition of Siah2 ubiquitin ligase by vitamin K3 (menadione) attenuates hypoxia and MAPK signaling and blocks melanoma tumorigenesis. Pigment cell & melanoma research 64 19712206
2012 The ubiquitin ligase Siah2 regulates PPARγ activity in adipocytes. Endocrinology 61 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
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 Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock. Proceedings of the National Academy of Sciences of the United States of America 33 26392558
2015 The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells. The Journal of biological chemistry 31 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
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 CHK2 stability is regulated by the E3 ubiquitin ligase SIAH2. Oncogene 26 26751770
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 24 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
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 ubiquitin ligase Siah2 regulates obesity-induced adipose tissue inflammation. Obesity (Silver Spring, Md.) 22 26380945
2015 The Expression of the Ubiquitin Ligase SIAH2 (Seven In Absentia Homolog 2) Is Increased in Human Lung Cancer. PloS one 22 26580787
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
2021 Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy. Frontiers in cell and developmental biology 20 33842469
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
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
2022 Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression. eLife 17 35913115
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
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
2020 Siah2 integrates mitogenic and extracellular matrix signals linking neuronal progenitor ciliogenesis with germinal zone occupancy. Nature communications 15 33082319
2016 Siah2 Protein Mediates Early Events in Commitment to an Adipogenic Pathway. The Journal of biological chemistry 15 27864366
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
2020 SIAH2 is Expressed in Adipocyte Precursor Cells and Interacts with EBF1 and ZFP521 to Promote Adipogenesis. Obesity (Silver Spring, Md.) 14 33155406
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
2019 Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge. Biology of sex differences 13 30987673
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
2023 CBX2-mediated suppression of SIAH2 triggers WNK1 accumulations to promote glycolysis in hepatocellular carcinoma. Experimental cell research 12 36780970
2022 SIAH2 regulates DNA end resection and replication fork recovery by promoting CtIP ubiquitination. Nucleic acids research 12 36155803
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
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 11 35816252
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
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
2023 YTHDF1 enhances stemness and chemoresistance in triple-negative breast cancer cells by upregulating SIAH2. Molecular carcinogenesis 9 37983722
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
2022 "The ubiquitin ligase SIAH2 is a female-specific regulator of circadian rhythms and metabolism". PLoS genetics 8 35789210
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 4 38842124
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 The deacetylases HDAC1/HDAC2 control JAK2V617F-STAT signaling through the ubiquitin ligase SIAH2. Signal transduction and targeted therapy 3 40877230
2024 SIAH2-Mediated Degradation of ACSL4 Inhibits the Anti-Tumor Activity of CD8+ T Cells in Hepatocellular Carcinoma. Critical reviews in eukaryotic gene expression 3 38842200
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 antagonism of Pard3/JamC modulates Ntn1-Dcc signaling to regulate cerebellar granule neuron germinal zone exit. Nature communications 2 39774925
2025 The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance. Cell death & disease 1 39875361
2025 SIAH2-AS1 stimulates breast cancer cell proliferation and migration via the Wnt/β-catenin signaling pathway. Scientific reports 1 40595045
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 is a lipid-mediated metabolic sensor in adipose tissue macrophage. Journal of lipid research 0 41690475
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