Affinage

ASB2

Ankyrin repeat and SOCS box protein 2 · UniProt Q96Q27

Length
635 aa
Mass
70.2 kDa
Annotated
2026-06-09
17 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/4 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASB2 is the substrate-recognition subunit of an ECS-type (Elongin BC–Cullin5–Rbx1) E3 ubiquitin ligase that drives polyubiquitination of bound substrates and their proteasomal degradation, coupling extracellular and developmental signals to targeted proteolysis (PMID:15590664). Through this complex ASB2 recognizes a substrate repertoire that includes the actin cross-linkers filamin A and filamin B, whose degradation inhibits cell spreading and underlies retinoic acid-induced myeloid differentiation (PMID:18799729), the BMP effector SMAD9, the cytoskeletal protein desmin, and NOX4 (PMID:34845242, PMID:40641155, PMID:41662915). ASB2 can also bridge non-canonical cullin assemblies, interacting with both Elongin BC–Cul5 and Skp2–Skp1–Cul1 to mediate degradation of E2A and JAK2 (PMID:21119685). Its transcription is directly induced by multiple signaling inputs—retinoic acid via RARα binding to a promoter RARE/RXRE element (PMID:11566180), Notch (PMID:30116272), the AHR (PMID:33717133), and FLI1 (PMID:34763718)—positioning ASB2 as a signal-responsive effector that regulates hematopoietic differentiation (PMID:18799729, PMID:11682484), NF-κB pathway activity through IκBα and RelB control (PMID:30116272, PMID:34763718), NK cell migration (PMID:33717133), BMP signaling during cardiogenesis (PMID:34845242), and skeletal muscle mass, where it acts as a negative regulator downstream of TGF-β/follistatin (PMID:27182554, PMID:40641155).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 Medium

    Established that ASB2 is a retinoic acid-responsive gene whose expression alone can recapitulate early commitment events of myeloid differentiation, linking it functionally to the RAR pathway before its biochemical activity was known.

    Evidence Ectopic ASB2 expression in myeloid leukemia cells with cell cycle/chromatin analysis; RARα ChIP and RARE/RXRE luciferase reporter on the ASB2 promoter

    PMID:11566180 PMID:11682484

    Open questions at the time
    • Molecular activity of ASB2 protein not yet defined
    • Direct substrates unknown at this stage
  2. 2004 High

    Defined the core biochemical identity of ASB2 as the specificity subunit of an ECS-type E3 ligase, answering how it acts mechanistically.

    Evidence In vitro reconstitution of ASB2–Elongin BC–Cul5–Rbx1 complex with Ubc5-dependent ubiquitination assay and co-IP

    PMID:15590664

    Open questions at the time
    • No physiological substrate identified in this study
    • Ubiquitin linkage type not characterized here
  3. 2008 High

    Identified filamin A/B as the first physiological substrates, connecting ASB2 ligase activity to actin remodeling and the differentiation phenotype previously observed.

    Evidence Reciprocal siRNA knockdown and overexpression in leukemia cells with filamin Western blots, cell spreading assays, and proteasome inhibitor rescue

    PMID:18799729

    Open questions at the time
    • Substrate recognition determinants not mapped
    • Whether filamin degradation fully accounts for differentiation effects unresolved
  4. 2010 Medium

    Extended the substrate range to E2A and JAK2 and showed ASB2 can bridge distinct cullin scaffolds (Cul1 via Skp2 and Cul5), revealing unexpected complex versatility downstream of Notch.

    Evidence Co-IP, dominant-negative Cul1/Cul5, and siRNA epistasis with substrate Western blots

    PMID:21119685

    Open questions at the time
    • Dual cullin model relies on a single lab
    • Direct ubiquitination of E2A/JAK2 not reconstituted in vitro
  5. 2018 Medium

    Placed ASB2 in the NF-κB axis by showing it degrades IκBα to activate NF-κB downstream of Notch1 in T-ALL.

    Evidence Lentiviral overexpression and shRNA knockdown in T-ALL lines with co-IP, Western blot, and proliferation/apoptosis assays

    PMID:30116272

    Open questions at the time
    • IκBα ubiquitination by ASB2 not directly reconstituted
    • Single cell-type context
  6. 2021 High

    Demonstrated substrate-selective ubiquitination of SMAD9 (not SMAD1/5) with in vivo developmental consequence, establishing an ASB2 role in BMP signaling and cardiogenesis.

    Evidence In vitro ubiquitination, co-IP, and zebrafish Asb2/Smad9 morpholino double-knockdown epistasis rescue

    PMID:34845242

    Open questions at the time
    • Basis of SMAD9 vs SMAD1/5 selectivity unknown
    • Mammalian cardiac requirement not tested here
  7. 2021 Medium

    Showed AHR and FLI1 as additional direct transcriptional drivers of ASB2, expanding its signal-responsive regulation and tying it to NK cell migration and DLBCL NF-κB biology.

    Evidence AHR and FLI1 ChIP/ChIP-seq at the ASB2 promoter, RNA-seq, and ASB2 knockdown with migration assays and NF-κB component Western blots

    PMID:33717133 PMID:34763718

    Open questions at the time
    • RelB regulation mechanism (direct vs indirect) not resolved
    • Single-lab findings per context
  8. 2025 Medium

    Provided in vivo genetic proof that ASB2 limits skeletal muscle mass and identified desmin as the relevant substrate, refining its role as a TGF-β/follistatin-controlled negative regulator of muscle.

    Evidence Muscle-specific Asb2 conditional knockout mice with strength/composition phenotyping plus siRNA-based desmin substrate identification; earlier AAV overexpression establishing the muscle-mass phenotype

    PMID:27182554 PMID:40641155

    Open questions at the time
    • Direct desmin ubiquitination not reconstituted in vitro
    • Contribution of desmin vs other substrates to hypertrophy not quantified
  9. 2026 Medium

    Revealed receptor-mediated substrate recruitment, with NDP52 delivering NOX4 to ASB2 for K48-linked degradation that suppresses cardiomyocyte ferroptosis.

    Evidence Co-IP, molecular docking, and genetic/pharmacological manipulation in cardiomyocytes plus in vivo TAC heart failure model

    PMID:41662915

    Open questions at the time
    • Mechanism of NDP52-ASB2 cooperation not structurally defined
    • Relative contribution of autophagic vs proteasomal degradation unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ASB2 achieves substrate selectivity across its diverse targets (filamins, SMAD9, JAK2, NOX4, desmin) and whether a unifying recognition motif or adaptor logic governs target choice remains unresolved.
  • No structural model of ASB2–substrate engagement
  • No defined degron consensus across substrates
  • Tissue-specific substrate prioritization mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 3 GO:0060089 molecular transducer activity 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2
Partners
CUL1CUL5ELOBELOCNDP52RBX1SKP2
Complex memberships
ECS (Elongin BC–Cullin5–Rbx1) E3 ubiquitin ligaseSkp2–Skp1–Cul1 (SCF) complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 ASB2 interacts with the Elongin BC complex and assembles with Cullin5 and Rbx1 to form an ECS-type E3 ubiquitin ligase complex that stimulates polyubiquitination by the E2 ubiquitin-conjugating enzyme Ubc5. Biochemical reconstitution of the E3 ligase complex; co-immunoprecipitation; in vitro ubiquitination assay The Journal of biological chemistry High 15590664
2008 ASB2 targets filamin A and filamin B for proteasomal degradation; knockdown of endogenous ASB2 in leukemia cells delays retinoic acid-induced differentiation and filamin degradation, while ASB2 expression induces filamin degradation and inhibits cell spreading. ASB2 knockdown (siRNA) and overexpression in leukemia cells; Western blot for filamin levels; cell spreading assay; proteasome inhibitor rescue Blood High 18799729
2001 ASB2 expression in myeloid leukemia cells induces growth inhibition and chromatin condensation, recapitulating early commitment events of retinoic acid-induced differentiation; ASB2 mRNA is a retinoic acid-induced target gene in APL cells with expression enhanced by PML-RARα. Ectopic expression of ASB2 in myeloid leukemia cells; cell cycle and chromatin condensation analysis; mRNA expression assays The Journal of biological chemistry Medium 11682484
2001 RARα binds to a functional RARE/RXRE element in the ASB2 gene promoter, directly driving ASB2 transcription in response to all-trans retinoic acid. Chromatin immunoprecipitation (RARα binding to ASB2 promoter); luciferase reporter assay of RARE/RXRE element FEBS letters Medium 11566180
2010 Notch signaling transcriptionally activates ASB2, which promotes ubiquitination and degradation of E2A (via Skp2) and JAK2 (by direct binding); ASB2 bridges non-canonical cullin-based complexes by interacting with Elongin B/C–Cul5 and also with the F-box protein Skp2–Skp1–Cul1, and dominant-negative Cul1 or Cul5, or their siRNA knockdown, protects E2A and JAK2 from ASB2-mediated degradation. Co-immunoprecipitation; dominant-negative mutant analysis; siRNA knockdown of Cul1/Cul5; Western blot for substrate levels Cell research Medium 21119685
2018 ASB2α induces degradation of IκBα, leading to dissociation of IκBα from NF-κB and consequent NF-κB activation in T-ALL cells downstream of Notch1. Lentiviral overexpression and shRNA knockdown of ASB2 in T-ALL cell lines; Western blot; co-immunoprecipitation; cell proliferation and apoptosis assays Cellular & molecular biology letters Medium 30116272
2021 ASB2 acts as the E3 ubiquitin ligase for SMAD9 (but not SMAD1 or SMAD5), targeting it for proteasomal degradation; this regulates BMP signaling during cardiogenesis, and Asb2 knockdown in zebrafish causes thinned ventricular wall and dilated ventricle that are rescued by simultaneous Smad9 knockdown. In vitro ubiquitination assay; co-immunoprecipitation; Asb2 and Smad9 morpholino knockdown in zebrafish with epistasis rescue experiment Scientific reports High 34845242
2021 AHR directly regulates the ASB2 gene promoter, and AHR agonist (FICZ) induces ASB2-dependent filamin A degradation in NK cells; ASB2 knockdown inhibits filamin A degradation and reduces NK cell migration, while filamin A reduction restores migration capacity. ChIP of AHR at ASB2 promoter; ASB2 knockdown in primary human NK cells; Western blot for filamin A; migration/invasion assays; Ahr-/- mouse NK cells Frontiers in immunology Medium 33717133
2021 ASB2 downregulation in GCB DLBCL cells inhibits the alternative NF-κB pathway via downregulation of RelB and increased IκBα, and ASB2 is a direct transcriptional target of FLI1 (identified by ChIP-seq and RNA-seq after FLI1 silencing). FLI1 ChIP-seq; RNA-seq after FLI1 siRNA knockdown; ASB2 siRNA knockdown with Western blot for NF-κB components Journal of experimental & clinical cancer research Medium 34763718
2016 ASB2 expression in skeletal muscle is repressed by follistatin (a TGF-β network modulator), and forced ASB2 overexpression reduces skeletal muscle mass, establishing ASB2 as a negative regulator of muscle mass downstream of TGF-β signaling. Quantitative proteomics and transcriptomics of follistatin-treated muscles; AAV-mediated overexpression of ASB2 in mouse skeletal muscle with muscle mass quantification JCI insight Medium 27182554
2025 Skeletal muscle-specific deletion of Asb2 increases muscle mass and strength; desmin was identified as a substrate of the ASB2 E3 ligase, with its preservation proposed to mediate the muscle hypertrophy phenotype. Conditional Asb2 knockout mice (Acta1-Cre); grip strength and body composition measurements; transcriptomic analysis; siRNA studies identifying desmin as an ASB2 substrate Journal of cachexia, sarcopenia and muscle Medium 40641155
2026 The autophagy receptor NDP52 recruits ASB2 to bind NOX4, mediating K48-linked ubiquitination and autophagic/proteasomal degradation of NOX4, thereby suppressing ferroptosis in cardiomyocytes; this was demonstrated in isoproterenol-induced (in vitro) and TAC-induced (in vivo) heart failure models. Co-immunoprecipitation; molecular docking; pharmacological and genetic (knockdown/knockout) approaches in cardiomyocytes; in vivo TAC model Free radical biology & medicine Medium 41662915
2024 ASB2 E3 ligase activity mediates K48-linked ubiquitination and degradation of CRYAB p.Arg120Gly aggregates in cardiomyocytes downstream of JAK1-STAT3 signaling; Asb2 knockdown abolishes the ability of ruxolitinib (JAK1/2 inhibitor) to clear CRYAB aggregates via the ubiquitin-proteasome system. siRNA knockdown of Asb2 in neonatal rat ventricular myocytes and hiPSC-CMs; aggregate quantification; RNAseq showing upregulation of Asb2 after Jak1 siRNA treatment; UPS inhibitor rescue experiments bioRxivpreprint Low bio_10.1101_2024.10.11.615348
2024 CHPF regulates SMAD9 activity via its mediation of ASB2; ASB2 ubiquitinates SMAD9, and CHPF's regulatory effect on SMAD9 in colorectal cancer cells is exerted through modulation of ASB2. Co-immunoprecipitation; knockdown experiments; Western blot for SMAD9 ubiquitination Histology and histopathology Low 38591191

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 ASB-2 inhibits growth and promotes commitment in myeloid leukemia cells. The Journal of biological chemistry 77 11682484
2008 ASB2 targets filamins A and B to proteasomal degradation. Blood 76 18799729
2004 ASB2 is an Elongin BC-interacting protein that can assemble with Cullin 5 and Rbx1 to reconstitute an E3 ubiquitin ligase complex. The Journal of biological chemistry 69 15590664
2001 ATRA-regulated Asb-2 gene induced in differentiation of HL-60 leukemia cells. FEBS letters 51 11566180
2000 Cloning and characterization of the genes encoding the ankyrin repeat and SOCS box-containing proteins Asb-1, Asb-2, Asb-3 and Asb-4. Gene 48 11111040
2016 Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass. JCI insight 45 27182554
2010 Notch-induced Asb2 expression promotes protein ubiquitination by forming non-canonical E3 ligase complexes. Cell research 43 21119685
2021 AHR Regulates NK Cell Migration via ASB2-Mediated Ubiquitination of Filamin A. Frontiers in immunology 27 33717133
2018 The notch pathway promotes NF-κB activation through Asb2 in T cell acute lymphoblastic leukemia cells. Cellular & molecular biology letters 23 30116272
2018 High-throughput analysis of the RNA-induced silencing complex in myotonic dystrophy type 1 patients identifies the dysregulation of miR-29c and its target ASB2. Cell death & disease 16 29955039
2021 ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma. Journal of experimental & clinical cancer research : CR 12 34763718
2021 ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis. Scientific reports 10 34845242
2021 Heart defects and embryonic lethality in Asb2 knock out mice correlate with placental defects. Cells & development 8 33993984
2025 Skeletal Muscle-Specific Deletion of E3 Ligase Asb2 Enhances Muscle Mass and Strength. Journal of cachexia, sarcopenia and muscle 4 40641155
2024 Chondroitin polymerizing factor (CHPF) promotes the progression of colorectal cancer through ASB2-mediated ubiquitylation of SMAD9. Histology and histopathology 4 38591191
2016 [Aberrant Expression Notch1 and Asb2 mRNA in Bone Marrow from Patients with P210(+) Chronic Myeloid Leukemia]. Zhongguo shi yan xue ye xue za zhi 1 27342488
2026 The autophagy receptor NDP52 recruits the E3 ligase ASB2 to mediate NOX4 degradation, suppressing cardiomyocyte ferroptosis and ameliorating heart failure. Free radical biology & medicine 0 41662915

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