Affinage

TAB2

TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 · UniProt Q9NYJ8

Length
693 aa
Mass
76.5 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 39 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

TAB2 is a ubiquitin-binding scaffold/adaptor protein that couples upstream immune-receptor signaling to activation of the kinase TAK1, driving NF-κB, JNK, and p38 MAPK responses downstream of IL-1R, TNFR, TLRs, RANK, and Edar (PMID:10882101, PMID:11809792, PMID:12609980, PMID:16251197). Upon IL-1 stimulation, TAB2 translocates from the membrane to the cytosol in an IRAK-dependent manner and bridges TAK1 to TRAF6, nucleating the TRAF6–TAK1–TAB1–TAB2 complex whose assembly and disassembly govern TAK1 activation (PMID:10882101, PMID:11259596, PMID:11518704, PMID:12242293). The central mechanistic basis is the C-terminal NZF zinc-finger domain, which binds preferentially to K63- (and K6-) linked polyubiquitin chains; crystal structures show two-site recognition of adjacent ubiquitin moieties via the Ile44 hydrophobic patch, with conformational constraints that select against linear chains, and mutations abolishing ubiquitin binding eliminate TAK1/IKK activation (PMID:15327770, PMID:19935683, PMID:19927120, PMID:34242591). TAB2 is functionally redundant with its paralog TAB3: single deletion leaves IL-1/TNF signaling largely intact, whereas combined loss impairs sustained TAK1, NF-κB, and MAPK activation, IκBζ expression, and macrophage cytokine production, with K63-ubiquitin binding by TAB2 required for full/sustained signaling (PMID:14633987, PMID:16260493, PMID:28507161, PMID:38567483). Beyond canonical inflammatory signaling, TAB2 scaffolds TAK1 to NLK to repress Wnt/β-catenin signaling (PMID:20194509), sequesters Beclin 1 to restrain autophagy until TAB2/TAB3 switch to engage TAK1 (PMID:22081109), and in cardiomyocytes mediates TAK1-dependent RIPK1 Ser321 phosphorylation that prevents apoptotic and necroptotic cell death; cardiomyocyte-specific TAB2 loss causes dilated cardiomyopathy rescued by RIPK1 kinase inactivation (PMID:34990405). TAB2 abundance and activity are tightly controlled by E3 ligases driving proteasomal or lysosomal degradation (TRIM30α, TRIM38, RBCK1, RNF4, TRIM22, RNF99) and by deubiquitinases (USP15, USP25) that stabilize it and potentiate signaling (PMID:18345001, PMID:24434549, PMID:17449468, PMID:26299341, PMID:23818111, PMID:31903660, PMID:37587766, PMID:36681779).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 High

    Established TAB2 as the adaptor that physically links TAK1 to TRAF6 in IL-1 signaling, defining its core scaffolding role in NF-κB/JNK activation.

    Evidence Co-IP, dominant-negative overexpression, and subcellular fractionation in IL-1-stimulated cells

    PMID:10882101

    Open questions at the time
    • Did not define the molecular determinant of the TRAF6 interaction
    • Did not establish whether the link is direct or ubiquitin-mediated
  2. 2002 High

    Resolved the temporal order of complex assembly, showing IRAK-dependent membrane recruitment of TRAF6 to pre-formed TAK1-TAB1-TAB2 followed by phosphorylation and cytosolic translocation.

    Evidence Sequential co-IP, subcellular fractionation, and phosphorylation assays in IRAK-deficient cells

    PMID:11259596 PMID:12242293

    Open questions at the time
    • Did not identify the signal triggering complex dissociation
    • Phosphorylation sites on TAB2 not mapped
  3. 2002 High

    Extended TAB2's adaptor role beyond IL-1R to RANK signaling, generalizing it across immune receptors.

    Evidence Co-IP and dominant-negative kinase assays in RANK-transfected and RAW264.7 cells

    PMID:11809792

    Open questions at the time
    • Did not address redundancy with TAB3 in this context
  4. 2003 High

    Knockout mice revealed TAB2 is dispensable for IL-1 signaling in fibroblasts but essential for fetal liver survival, separating signaling redundancy from an anti-apoptotic role.

    Evidence TAB2 knockout mouse with embryonic phenotyping and MEF signaling assays

    PMID:12556483

    Open questions at the time
    • Mechanism of the anti-apoptotic liver function not defined
    • Redundant factor compensating in MEFs not yet identified
  5. 2003 High

    Identified TAB3 as a functionally redundant paralog, explaining why single TAB2 loss is tolerated and that both are ubiquitinated via TRAF6.

    Evidence siRNA double knockdown, co-IP, and ubiquitination assays

    PMID:14633987

    Open questions at the time
    • Did not establish the linkage type of TAB2/TAB3 ubiquitination
    • Functional consequence of TAB2 ubiquitination unclear
  6. 2004 High

    Defined the mechanistic core: the NZF zinc finger binds K63-linked polyubiquitin and this binding is necessary and sufficient (via domain swap) for TAK1/IKK activation.

    Evidence In vitro ubiquitin binding, mutagenesis, and heterologous domain-swap rescue with co-IP

    PMID:15327770

    Open questions at the time
    • Structural basis of K63 selectivity not yet resolved
    • Physiological ubiquitinated targets only partly defined (RIP)
  7. 2005 High

    Genetic dissection placed TAK1 as essential and TAB2/TAB1 as individually dispensable across TNFR1/IL-1R/TLR signaling, clarifying the division of labor in the complex.

    Evidence Conditional knockout MEFs with NF-κB/AP-1 reporter and kinase assays

    PMID:16260493

    Open questions at the time
    • Did not test combined TAB2/TAB3 loss
    • In vivo immune consequences not addressed
  8. 2006 High

    Mapped reciprocal binding interfaces between TAB2 (residues 574–693) and TAK1 (residues 479–553), enabling a disrupting peptide that blocks signaling and osteoclast differentiation.

    Evidence Deletion mapping, co-IP, dominant-negative peptide, and osteoclast differentiation assays

    PMID:17158449

    Open questions at the time
    • Did not provide atomic structure of the interface
  9. 2009 High

    Crystal structures explained K63 selectivity by showing two-site recognition of adjacent ubiquitins via the Ile44 patch with conformational constraints incompatible with linear chains.

    Evidence X-ray crystallography of NZF–K63 di/triubiquitin complexes with mutagenesis

    PMID:19927120 PMID:19935683

    Open questions at the time
    • Did not address binding to other non-K63 linkages such as K6
  10. 2009 High

    Revealed a non-inflammatory scaffolding role, recruiting calcineurin/RCAN1 to TAK1 so that TAK1 phosphorylates RCAN1 to facilitate calcineurin-NFAT signaling.

    Evidence Yeast two-hybrid, in vitro kinase reconstitution, mutagenesis, and Tab2-deficient MEFs

    PMID:19136967

    Open questions at the time
    • Physiological tissue context of this module not defined
  11. 2010 Medium

    Extended TAB2 scaffolding to Wnt repression by bridging TAK1 to NLK to drive LEF1 ubiquitylation and inhibit β-catenin signaling.

    Evidence Co-IP, domain mapping (residues 292–417), siRNA, and luciferase reporter

    PMID:20194509

    Open questions at the time
    • Single lab
    • In vivo relevance to Wnt-dependent processes not tested
  12. 2011 High

    Identified a TAB2/TAB3-Beclin 1 interaction that restrains autophagy, with a switch in which TAB2/TAB3 dissociate from Beclin 1 to engage TAK1 upon autophagy induction.

    Evidence Co-IP, coiled-coil domain mapping, siRNA/overexpression with autophagy readouts

    PMID:22081109

    Open questions at the time
    • Trigger that releases TAB2 from Beclin 1 not defined
    • Direct effect on Beclin 1 function unresolved
  13. 2008 High

    Established degradative regulation of TAB2 by demonstrating TRIM30α-mediated degradation in an NF-κB-dependent negative-feedback loop.

    Evidence Co-IP, degradation assay, siRNA, and transgenic mouse with NF-κB reporter

    PMID:18345001

    Open questions at the time
    • Ubiquitin linkage on TAB2 not specified
    • Degradation route (proteasome vs lysosome) not defined here
  14. 2014 High

    Distinguished lysosomal from proteasomal turnover, showing TRIM38 drives ligase-activity-independent lysosomal degradation of TAB2 to dampen TAK1 activation.

    Evidence Co-IP, lysosomal inhibitor assay, TRIM38 knockout cells, and RING-domain mutant

    PMID:24434549

    Open questions at the time
    • Trafficking machinery routing TAB2 to lysosomes not defined
  15. 2023 High

    Defined site-specific proteasomal control via RNF99-mediated K48 ubiquitination of TAB2 at Lys611 with an in vivo TLR hyperresponsiveness phenotype.

    Evidence Co-IP, K48-ubiquitination assay, K611 mutagenesis, and RNF99 knockout mouse

    PMID:36681779

    Open questions at the time
    • Stimulus controlling RNF99 engagement of TAB2 not defined
  16. 2020 Medium

    Identified deubiquitinase counter-regulation, showing USP15 (K48 removal plus a DUB-independent block of lysosomal degradation) and later USP25 (K63 removal) tune TAB2 stability and signaling output.

    Evidence Deubiquitination assays, co-IP, lysosomal inhibitor assays, and NF-κB reporter; USP25 with in vivo AAV9 knockdown

    PMID:31903660 PMID:37587766

    Open questions at the time
    • Single lab per DUB
    • Interplay between opposing E3/DUB activities not reconstituted
  17. 2017 High

    Quantified the contribution of K63-ubiquitin binding to signaling duration, showing TAB2/TAB3 are needed for sustained (not initial) TAK1 activation and that the binding-defective mutant fails to rescue triple-knockout cells.

    Evidence TAB2/TAB3 double- and TAB1/2/3 triple-knockout cells with ubiquitin-binding mutant reconstitution and kinase assays

    PMID:28507161

    Open questions at the time
    • Mechanism converting ubiquitin binding into sustained kinase output not fully defined
  18. 2022 High

    Revealed a cardioprotective cell-death function in which TAB2 mediates TAK1-dependent RIPK1 Ser321 phosphorylation to suppress apoptosis and necroptosis, with loss causing dilated cardiomyopathy.

    Evidence Cardiomyocyte-specific knockout, RIPK1 phosphorylation assay, RIPK1-K45A knockin rescue, and death-complex IP

    PMID:34990405

    Open questions at the time
    • Whether TAB2's ubiquitin binding is required for RIPK1 regulation not isolated
    • Generality beyond cardiomyocytes untested
  19. 2024 High

    Resolved earlier conflicting redundancy data with an improved double-knockout model, confirming TAB2/TAB3 are redundantly required for TLR-driven NF-κB/MAPK activation, IκBζ expression, and IL-6 production in macrophages.

    Evidence TAB2/TAB3 double-knockout macrophages with cytokine and signaling assays and IκBζ analysis

    PMID:38567483

    Open questions at the time
    • Mechanism by which TAB2/TAB3 control IκBζ transcription not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse non-canonical TAB2 functions (calcineurin-NFAT, NLK-Wnt, Beclin 1-autophagy, RIPK1 cell death, ERα corepressor dismissal) are coordinated with its canonical ubiquitin-dependent TAK1 scaffolding, and which require NZF ubiquitin binding, remains unresolved.
  • No unifying model linking ubiquitin binding to the non-TAK1 functions
  • Tissue- and stimulus-specific partitioning of TAB2 functions not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
BECN1NLKRCAN1RIPK1TAB1TAK1TRAF2TRAF6
Complex memberships
TAK1-TAB1-TAB2 kinase complexTRAF6-TAK1-TAB1-TAB2 complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TAB2 is an adaptor protein that physically links TAK1 to TRAF6 in the IL-1 signaling pathway. IL-1 stimulation induces translocation of TAB2 from the membrane to the cytosol, where it mediates IL-1-dependent association of TAK1 with TRAF6, leading to TAK1 activation and downstream JNK and NF-κB activation. Dominant-negative TAB2 impairs JNK and NF-κB activation by IL-1. Co-immunoprecipitation, dominant-negative overexpression, subcellular fractionation Molecular cell High 10882101
2001 IRAK is required for IL-1-induced TAB2 translocation from the membrane to the cytosol. In IRAK-deficient cells, TAB2 translocation and its association with TRAF6 are abolished, preventing formation of the TRAF6-TAB2-TAK1 complex and TAK1 activation. IRAK-deficient cell lines, subcellular fractionation, co-immunoprecipitation Molecular and cellular biology High 11259596 11518704
2002 In IL-1 signaling, IRAK recruits TRAF6 to a membrane complex (complex I), which then associates with pre-formed TAK1-TAB1-TAB2 on the membrane (complex II). This leads to phosphorylation of TAK1 and TAB2 on the membrane, followed by dissociation of the TRAF6-TAK1-TAB1-TAB2 complex (complex III) and translocation to the cytosol where TAK1 is activated. Sequential co-immunoprecipitation, subcellular fractionation, phosphorylation assays with IRAK-deficient cells Molecular and cellular biology High 12242293
2002 TAK1 and TAB2 participate in the RANK signaling pathway. RANKL stimulation promotes formation of a complex containing RANK, TRAF6, TAB2, and TAK1, leading to TAK1 activation. Dominant-negative TAB2 inhibits NF-κB activation induced by RANK overexpression and by RANKL in monocyte RAW264.7 cells. Co-immunoprecipitation in RANK-stably transfected 293 cells, dominant-negative overexpression, kinase assay Molecular and cellular biology High 11809792
2003 TLR3-mediated NF-κB and MAP kinase activation proceeds through an IRAK-independent pathway in which TRAF6, TAK1, and TAB2 are recruited to the TLR3 receptor to form a complex that translocates to the cytosol where TAK1 is phosphorylated and activated. PKR is also detected in this TAK1 complex. IRAK-deficient cell lines, co-immunoprecipitation, subcellular fractionation, dominant-negative kinase assays The Journal of biological chemistry High 12609980
2003 TAB2-deficient mouse embryonic fibroblasts do not show impaired IL-1-induced NF-κB or MAP kinase activation, demonstrating that TAB2 alone is not essential for IL-1 signaling in fibroblasts. However, TAB2 knockout is embryonic lethal due to liver degeneration and apoptosis, indicating an essential anti-apoptotic role in fetal liver. TAB2 knockout mouse generation, embryonic fibroblast NF-κB activation assays Molecular and cellular biology High 12556483
2003 TAB3, a TAB2-like molecule, associates with TAK1 and activates NF-κB. Endogenous TAB3 interacts with TRAF6 and TRAF2 in an IL-1- and TNF-dependent manner, respectively. IL-1 signaling leads to ubiquitination of TAB2 and TAB3 through TRAF6. siRNA knockdown of both TAB2 and TAB3 (but not either alone) inhibits IL-1- and TNF-induced TAK1 and NF-κB activation, showing functional redundancy. siRNA double knockdown, co-immunoprecipitation, ubiquitination assay The EMBO journal High 14633987
2004 TAB2 and TAB3 bind preferentially to lysine 63-linked polyubiquitin chains through a conserved C-terminal zinc finger (NZF/ZnF) domain. Mutations of the ZnF domain abolish polyubiquitin binding and the ability to activate TAK1 and IKK. Replacement of the ZnF domain with a heterologous ubiquitin-binding domain restores TAK1 and IKK activation. TAB2 binds to polyubiquitinated RIP following TNF-α stimulation. In vitro ubiquitin-binding assay, site-directed mutagenesis, domain swap experiments, co-immunoprecipitation Molecular cell High 15327770
2004 TAB2 is involved in the phosphorylation of TAK1 at Thr-187 in the activation loop during TNF-α stress. TAB1 and TAB2 regulate TAK1 Thr-187 phosphorylation differentially. TAB2 is part of the TAK1 signaling complex required for stress-induced rapid and transient TAK1 activation. Phospho-specific antibody, RNA interference, overexpression experiments, kinase assays The Journal of biological chemistry Medium 15590691
2005 TAK1 (but not TAB1 or TAB2 alone) is essential for TNFR1-, IL-1R-, TLR3-, and TLR4-mediated NF-κB and AP-1 activation in embryonic fibroblasts. Tab1(-/-) and Tab2(-/-) fibroblasts show normal NF-κB and AP-1 responses, confirming the redundant/dispensable roles of TAB1 and TAB2 in these contexts. Conditional knockout mouse embryonic fibroblasts, NF-κB luciferase assays, kinase assays Genes & development High 16260493
2005 TAB2, TRAF6, and TAK1 are components of the Edar/Edaradd NF-κB signaling pathway. TAB2 was identified as a binding partner of Edaradd by yeast two-hybrid; endogenous TAB2, TRAF6, and TAK1 co-immunoprecipitate with Edaradd. Dominant-negative TAB2, TRAF6, and TAK1 block NF-κB activation by Edaradd. Yeast two-hybrid, co-immunoprecipitation, dominant-negative functional assay Human molecular genetics Medium 16251197
2005 Drosophila TAB2 (dTAB2) links dTRAF1 to the JNKKK dTAK1, functioning as an adaptor in the TNF/Eiger-JNK pathway. Genetic epistasis and biochemical protein-protein interaction assays establish dTAB2 as an essential component of this conserved signaling module. Genetic screen, epistasis analysis, protein-protein interaction assay Genetics Medium 16079232
2006 The TAB2/TAB3-binding domain in TAK1 maps to a non-contiguous region in the last C-terminal 100 residues (residues 479–553 are necessary and sufficient). Residues 574–693 of TAB2 interact with TAK1. A peptide (TAK1-C100) that disrupts TAB2/TAB3-TAK1 interaction abolishes TAK1 phosphorylation and IKK/MAPK activation by IL-1, TNF, and RANKL, and blocks RANKL-induced osteoclast differentiation. Deletion mapping, co-immunoprecipitation, dominant-negative peptide, kinase assays, osteoclast differentiation assay The Journal of biological chemistry High 17158449
2007 Smad7 binds directly to TAB2 and TAB3, competing with TAK1 binding and blocking recruitment of TAK1 to TRAF2 in the TNF signaling pathway. Smad7-TAB2/TAB3 complex formation suppresses TNF-induced NF-κB activation. Transgenic Smad7 in mouse skin disrupts endogenous TRAF2-TAK1-TAB2 complex formation. Co-immunoprecipitation, in vitro binding assay, transgenic mouse model, NF-κB reporter assays Nature immunology High 17384642
2007 HTLV-1 Tax physically interacts with TAB2; TAB2 and Tax cooperatively activate TAK1, and TAK1 activation by Tax requires TAB2 binding as well as ubiquitination of Tax. Tax-induced overexpression of TAB2 (but not TAB3) leads to constitutive TAK1 activation, which drives JNK-ATF2 but not IKK-NF-κB signaling. Co-immunoprecipitation, siRNA knockdown, kinase assays, reporter assays The Journal of biological chemistry / Biochemical and biophysical research communications Medium 17626013 17986383
2008 TRIM30α promotes degradation of TAB2 and TAB3 through its RING domain E3 ubiquitin ligase activity. TRIM30α interacts with the TAB2-TAB3-TAK1 complex and negatively regulates TLR-mediated NF-κB activation via this degradation. Expression of TRIM30α is itself NF-κB-dependent, forming a negative feedback loop. Co-immunoprecipitation, protein degradation assay, siRNA knockdown, transgenic mouse, NF-κB reporter Nature immunology High 18345001
2008 NUMBL interacts with TAB2 via its PTB domain. NUMBL overexpression inhibits TNF-α- and IL-1β-induced NF-κB activation and impairs TAB2 binding to TRAF6 or RIP, and inhibits TRAF6 ubiquitination enhanced by TAB2. Yeast two-hybrid, co-immunoprecipitation (in vitro and in vivo), NF-κB reporter, ubiquitination assay Cellular signalling Medium 18299187
2009 Crystal structures of the TAB2 NZF domain bound to K63-linked di- and triubiquitin reveal that TAB2 binds adjacent ubiquitin moieties via two distinct binding sites. Both sites recognize the Ile44-centered hydrophobic patch on ubiquitin but do not contact the K63 isopeptide bond. The conformational constraints imposed by TAB2 on K63 dimers cannot be adopted by linear chains, explaining selectivity for K63 over linear ubiquitin chains. X-ray crystallography, mutagenesis of binding sites, ubiquitin-binding assay Nature structural & molecular biology High 19935683
2009 Crystal structures of TAB2 and TAB3 NZF domains in complex with K63-linked diubiquitin at 1.18 and 1.40 Å resolution confirm two-site binding: distal ubiquitin recognized via conserved Thr-Phe dipeptide; proximal ubiquitin via a surface specific to TAB2/TAB3. Mutagenesis shows both sites are required for K63-linked diubiquitin binding. X-ray crystallography, mutagenesis, ubiquitin-binding assay The EMBO journal High 19927120
2009 TAB2 was identified as a direct binding partner of RCAN1 by yeast two-hybrid. TAB2 recruits TAK1, TAB1, and calcineurin, forming a macromolecular signaling complex. TAK1 (activated via TAB1 and TAB2) phosphorylates RCAN1 at Ser94 and Ser136, converting RCAN1 from an inhibitor to a facilitator of calcineurin-NFAT signaling. In Tab2-deficient MEFs, the TAK1-TAB1-TAB2 and calcineurin-NFAT modules do not interact. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, Tab2-deficient MEFs Nature cell biology High 19136967
2010 TAB2 functions as a scaffold protein that directly interacts with NLK and bridges TAK1 to NLK. The intermediate region (residues 292–417) of TAB2 is required for NLK binding. TAB2 mediates TAK1-dependent NLK activation and LEF1 polyubiquitylation, resulting in inhibition of canonical Wnt/β-catenin signaling. Wnt3a stimulation increases TAB2-NLK interaction and promotes TAK1-TAB2-NLK complex formation. Co-immunoprecipitation, siRNA knockdown, deletion mutant analysis, luciferase reporter assay The Journal of biological chemistry Medium 20194509
2011 Beclin 1 constitutively interacts with TAB2 and TAB3 via their coiled-coil domains. Upon autophagy induction, TAB2 and TAB3 dissociate from Beclin 1 and bind TAK1. Overexpression of TAB2/TAB3 suppresses autophagy, while their depletion triggers autophagy. This defines an autophagy-stimulatory switch where TAB2/TAB3 abandon inhibitory interactions with Beclin 1 to engage TAK1. Co-immunoprecipitation, siRNA knockdown, autophagy assays, domain mapping (coiled-coil domain) The EMBO journal High 22081109
2011 TAB2 interaction with TAK1 attenuates the ASK1-TAK1 interaction through competitive binding at the C-terminal TAB2-binding domain of TAK1, thereby reciprocally regulating both TAK1-NF-κB and ASK1-AP-1 signaling pathways. Co-immunoprecipitation, competitive binding assays, kinase assays, reporter assays The Journal of biological chemistry Medium 22167179
2013 TAB2 undergoes SUMOylation at the conserved lysine 329, mediated by the SUMO E3 ligase PIAS3. Mutation of K329 blocks SUMOylation and enhances TAB2 activity as measured by AP-1 luciferase reporter assays, indicating that SUMOylation negatively regulates TAB2 activity. SUMOylation assay, Ubc9 fusion analysis, site-directed mutagenesis (K329), co-immunoprecipitation with PIAS3, AP-1 reporter Molecular and cellular biochemistry Medium 24096733
2014 TRIM38 constitutively interacts with TAB2 and TAB3 and promotes their lysosome-dependent degradation, independent of TRIM38's E3 ubiquitin ligase activity. TRIM38 deficiency abolishes TAB2 translocation to the lysosome, increases TAB2 levels, and enhances TAK1 activation after TNF-α and IL-1β stimulation. Co-immunoprecipitation, lysosomal inhibitor assays, TRIM38 knockout cells, TRIM38 RING-domain mutant Proceedings of the National Academy of Sciences of the United States of America High 24434549
2014 Enterovirus 71 3C protease cleaves TAB2 at Q113-S114, requiring protease activity (abolished by H40D or C147S active-site substitutions). 3C interacts with TAB2 and TAK1, inhibiting NF-κB activation. Overexpression of TAB2 inhibits EV71 replication, while cleaved fragments have no effect. Co-immunoprecipitation, protease active-site mutagenesis, cleavage-site mapping, overexpression rescue assay Journal of virology High 24942571
2015 RBCK1 physically interacts with TAB2 and TAB3 and facilitates their degradation through a proteasome-dependent process, negatively regulating TNF- and IL-1-induced NF-κB activation. Co-immunoprecipitation, proteasome inhibitor assay, siRNA knockdown, NF-κB reporter The Journal of biological chemistry Medium 17449468
2015 RNF4 interacts with the TAK1-TAB2-TAB3 complex (but not TAB1) and specifically down-regulates TAB2 through a lysosomal pathway, negatively regulating NF-κB signaling. Co-immunoprecipitation, lysosomal inhibitor assay, siRNA knockdown, NF-κB reporter FEBS letters Medium 26299341
2015 TRIM22 interacts with TAB2 and promotes its degradation, negatively regulating the TRAF6-stimulated NF-κB pathway. The RING domain of TRIM22 is required for these effects. Co-immunoprecipitation, protein degradation assay, RING-domain deletion mutant, NF-κB reporter Virologica Sinica Medium 23818111
2016 TAB2 interacts with estrogen receptor alpha (ERα) through a central domain (residues adjacent to MEKK1 phosphorylation sites, distinct from the NZF and CUE domains). This interaction dismisses NCoR corepressor from ERα on target gene regulatory regions, contributing to tamoxifen resistance. siRNA knockdown of TAB2 restores antiproliferative response to tamoxifen in resistant breast cancer cells. Co-immunoprecipitation, pull-down with recombinant proteins, competition assay, domain mapping, siRNA knockdown, cell proliferation assay PloS one / Oncogene Medium 22249258 27992601
2017 IL-1β can activate the TAB1-TAK1 heterodimer in TAB2/TAB3 double knockout cells, but this activation requires TRAF6 expression and Ubc13 (K63-Ub chain synthesis). In TAB2/3 DKO cells, early NF-κB and p38α activation is normal but is transient, and JNK1/2 and p38γ activation is greatly reduced. An ubiquitin-binding-defective mutant of TAB2 cannot restore signaling to TAB1/2/3 triple KO cells, confirming that K63-Ub chain binding by TAB2 is required for sustained/full TAK1 signaling. TAB2/TAB3 double knockout cells, TAB1/2/3 triple knockout cells, ubiquitin-binding mutant reconstitution, kinase assays, siRNA knockdown The Biochemical journal High 28507161
2019 Multiple GPCR agonists (thrombin, histamine) activate p38 MAPK via a non-canonical, TAB1-TAB2-dependent pathway (rather than canonical MKK3/6) in endothelial cells. In different endothelial cell types, either TAB1-TAB2 or TAB1-TAB3, or both, are required for GPCR-stimulated p38 autophosphorylation and IL-6 production. siRNA knockdown of TAB1, TAB2, TAB3; phosphorylation assays; IL-6 production assay; multiple endothelial cell types The Journal of biological chemistry Medium 30760523
2020 USP15 deubiquitinates K48-linked ubiquitin chains from TAB2 (and independently inhibits lysosome-associated TAB2 degradation via a deubiquitinase-independent mechanism), thereby stabilizing TAB2, enhancing TAK1-TAB complex integrity, and potentiating NF-κB activation following TNF-α and IL-1β stimulation. Co-immunoprecipitation, deubiquitination assay, lysosomal inhibitor assay, siRNA knockdown/overexpression, NF-κB reporter The FEBS journal Medium 31903660
2021 Crystal structure of TAB2 NZF in complex with K6-linked diubiquitin at 1.99 Å resolution reveals that TAB2-NZF simultaneously contacts distal and proximal ubiquitin moieties of K6-Ub2. Structural comparison with K63-Ub2 complex shows similar binding mechanism except for flexibility in the C-terminal region of the distal ubiquitin, which accounts for dual K6/K63 specificity. X-ray crystallography, structural comparison, mutagenesis Biophysical journal High 34242591
2022 Cardiomyocyte-specific deletion of TAB2 (but not TAB3) in mice causes dilated cardiomyopathy with massive apoptotic and necroptotic cell death. TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, preventing RIPK1 kinase activation and formation of RIPK1-FADD-caspase-8 apoptotic and RIPK1-RIPK3 necroptotic complexes. Genetic inactivation of RIPK1 (Ripk1-K45A knockin) rescues cardiac remodeling in Tab2-deficient mice. Cardiomyocyte-specific TAB2 knockout, RIPK1 phosphorylation assay, RIPK1-K45A knockin rescue, complex immunoprecipitation, apoptosis/necroptosis assays The Journal of clinical investigation High 34990405
2023 USP25 deubiquitinates K63-specific polyubiquitin chains from TAB2, restricting NF-κB and MAPK signaling activation. AAV9-mediated TAB2 knockdown ameliorates ischemic stroke injury and abolishes the effect of USP25 deletion, placing USP25-TAB2 axis in neuroinflammatory regulation. Co-immunoprecipitation, K63-deubiquitination assay, AAV9-mediated knockdown in vivo, NF-κB/MAPK signaling assays Advanced science Medium 37587766
2023 RNF99 promotes K48-linked ubiquitination of TAB2 at lysine 611, leading to proteasomal degradation of TAB2 and negative regulation of TLR-mediated NF-κB and MAPK signaling. RNF99 knockout mice show enhanced TLR-mediated cytokine production. Co-immunoprecipitation, K48-ubiquitination assay, site-directed mutagenesis (K611), RNF99 knockout mouse, proteasomal inhibitor assay Cell death and differentiation High 36681779
2024 TAB2 and TAB3 are redundantly required for TLR-mediated cytokine production (TNF-α, IL-6) in macrophages. TAB2/TAB3 double-deficient macrophages show significantly impaired NF-κB and MAPK pathway activation, and severely compromised IκBζ expression at both protein and mRNA levels, thereby impeding IL-6 production. TAB2/TAB3 double knockout macrophages (improved mouse model), cytokine assays, NF-κB and MAPK signaling assays, IκBζ expression analysis International immunology High 38567483
2025 LSDV001 viral protein interacts with TAK1 and TAB2/TAB3 and promotes assembly of the TAK1-TAB2/3 complex, leading to enhanced IKK-dependent NF-κB activation and inflammatory cytokine induction. LSDV001-deficient virus has attenuated NF-κB activation and reduced pathology. Co-immunoprecipitation, NF-κB reporter, virus deletion mutant (LSDVΔ001), in vivo infection model mBio Medium 40852992

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Molecular cell 749 15327770
2005 TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes & development 622 16260493
2000 TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Molecular cell 515 10882101
2012 The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α. Nature medicine 372 22660635
2003 Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR . The Journal of biological chemistry 245 12609980
2003 Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. The EMBO journal 239 14633987
2002 Receptor activator of NF-kappaB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Molecular and cellular biology 236 11809792
2002 Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. Molecular and cellular biology 233 12242293
2008 TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation. Nature immunology 215 18345001
2004 Critical roles of threonine 187 phosphorylation in cellular stress-induced rapid and transient activation of transforming growth factor-beta-activated kinase 1 (TAK1) in a signaling complex containing TAK1-binding protein TAB1 and TAB2. The Journal of biological chemistry 186 15590691
2009 Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain. Nature structural & molecular biology 180 19935683
2001 IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B. The Journal of biological chemistry 174 11518704
2001 Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway. Molecular and cellular biology 161 11259596
2014 TRIM38 inhibits TNFα- and IL-1β-triggered NF-κB activation by mediating lysosome-dependent degradation of TAB2/3. Proceedings of the National Academy of Sciences of the United States of America 125 24434549
2007 Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2. Nature immunology 123 17384642
2009 Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by NZF domains of TAB2 and TAB3. The EMBO journal 121 19927120
2006 TAK1-dependent signaling requires functional interaction with TAB2/TAB3. The Journal of biological chemistry 120 17158449
2009 Interaction between TAK1-TAB1-TAB2 and RCAN1-calcineurin defines a signalling nodal control point. Nature cell biology 113 19136967
2003 TAB2 is essential for prevention of apoptosis in fetal liver but not for interleukin-1 signaling. Molecular and cellular biology 109 12556483
2010 Haploinsufficiency of TAB2 causes congenital heart defects in humans. American journal of human genetics 88 20493459
2014 Enterovirus 71 3C inhibits cytokine expression through cleavage of the TAK1/TAB1/TAB2/TAB3 complex. Journal of virology 86 24942571
2005 TAB2, TRAF6 and TAK1 are involved in NF-kappaB activation induced by the TNF-receptor, Edar and its adaptator Edaradd. Human molecular genetics 85 16251197
2011 Inhibition of autophagy by TAB2 and TAB3. The EMBO journal 84 22081109
2005 Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves' disease. The Journal of clinical endocrinology and metabolism 78 16384851
2007 RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation. The Journal of biological chemistry 66 17449468
2020 USP15 potentiates NF-κB activation by differentially stabilizing TAB2 and TAB3. The FEBS journal 60 31903660
2010 IFN-γ and TNF-α synergistically induce microRNA-155 which regulates TAB2/IP-10 expression in human mesangial cells. American journal of nephrology 54 20948191
2005 A genetic screen targeting the tumor necrosis factor/Eiger signaling pathway: identification of Drosophila TAB2 as a functionally conserved component. Genetics 54 16079232
2023 MicroRNAs of extracellular vesicles derived from mesenchymal stromal cells alleviate inflammation in dry eye disease by targeting the IRAK1/TAB2/NF-κB pathway. The ocular surface 53 36990276
2013 Essential roles of K63-linked polyubiquitin-binding proteins TAB2 and TAB3 in B cell activation via MAPKs. Journal of immunology (Baltimore, Md. : 1950) 52 23509369
2005 Drosophila TAB2 is required for the immune activation of JNK and NF-kappaB. Cellular signalling 49 16311020
2004 A 212-kb region on chromosome 6q25 containing the TAB2 gene is associated with susceptibility to type 1 diabetes. Diabetes 44 15220215
2019 G protein-coupled receptors activate p38 MAPK via a non-canonical TAB1-TAB2- and TAB1-TAB3-dependent pathway in endothelial cells. The Journal of biological chemistry 42 30760523
2018 TRIM38 regulates NF-κB activation through TAB2 degradation in osteoclast and osteoblast differentiation. Bone 42 29753717
2013 TRIM22 inhibits the TRAF6-stimulated NF-κB pathway by targeting TAB2 for degradation. Virologica Sinica 42 23818111
2022 TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis. The Journal of clinical investigation 40 34990405
2023 USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 38 37587766
2017 Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3. The Biochemical journal 37 28507161
2011 TAK1-TAB2 signaling contributes to bone destruction by breast carcinoma cells. Molecular cancer research : MCR 36 21700681
2005 Functional variants in SUMO4, TAB2, and NFkappaB and the risk of type 1 diabetes. Genes and immunity 35 15729364
2017 NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes. FEBS letters 33 28295271
2020 Drosophila Myc restores immune homeostasis of Imd pathway via activating miR-277 to inhibit imd/Tab2. PLoS genetics 30 32810129
2010 TAB2 scaffolds TAK1 and NLK in repressing canonical Wnt signaling. The Journal of biological chemistry 30 20194509
2012 Targeting of the adaptor protein Tab2 as a novel approach to revert tamoxifen resistance in breast cancer cells. Oncogene 29 22249258
2007 Constitutive activation of TAK1 by HTLV-1 tax-dependent overexpression of TAB2 induces activation of JNK-ATF2 but not IKK-NF-kappaB. The Journal of biological chemistry 29 17626013
2021 Circ_AFF2 facilitates proliferation and inflammatory response of fibroblast-like synoviocytes in rheumatoid arthritis via the miR-375/TAB2 axis. Experimental and molecular pathology 27 33535081
2015 Identification and functional characterization of the TAB2 gene from Litopenaeus vannamei. Fish & shellfish immunology 27 26102459
2007 HTLV-1 Tax-mediated TAK1 activation involves TAB2 adapter protein. Biochemical and biophysical research communications 27 17986383
2021 TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility. European journal of human genetics : EJHG 26 34456334
2016 Interleukin-17A inhibits cell autophagy under starvation and promotes cell migration via TAB2/TAB3-p38 mitogen-activated protein kinase pathways in hepatocellular carcinoma. European review for medical and pharmacological sciences 26 26875893
2011 Reciprocal inhibition between the transforming growth factor-β-activated kinase 1 (TAK1) and apoptosis signal-regulating kinase 1 (ASK1) mitogen-activated protein kinase kinase kinases and its suppression by TAK1-binding protein 2 (TAB2), an adapter protein for TAK1. The Journal of biological chemistry 26 22167179
2008 NUMBL interacts with TAB2 and inhibits TNFalpha and IL-1beta-induced NF-kappaB activation. Cellular signalling 26 18299187
2017 6q25.1 (TAB2) microdeletion syndrome: Congenital heart defects and cardiomyopathy. American journal of medical genetics. Part A 25 28464518
2015 RNF4 negatively regulates NF-κB signaling by down-regulating TAB2. FEBS letters 25 26299341
2019 MiR-142a-3p alleviates Escherichia coli derived lipopolysaccharide-induced acute lung injury by targeting TAB2. Microbial pathogenesis 24 31494298
2015 Phosphoinositide-dependent kinase-1 inhibits TRAF6 ubiquitination by interrupting the formation of TAK1-TAB2 complex in TLR4 signaling. Cellular signalling 24 26432169
2022 Selective autophagy controls innate immune response through a TAK1/TAB2/SH3PX1 axis. Cell reports 23 35081354
2020 Antagonism of Protease-Activated Receptor 4 Protects Against Traumatic Brain Injury by Suppressing Neuroinflammation via Inhibition of Tab2/NF-κB Signaling. Neuroscience bulletin 23 33111257
2021 Hepatitis B Surface Antigen Suppresses the Activation of Nuclear Factor Kappa B Pathway via Interaction With the TAK1-TAB2 Complex. Frontiers in immunology 22 33717111
2021 microRNA-149-5p mediates the PM2.5-induced inflammatory response by targeting TAB2 via MAPK and NF-κB signaling pathways in vivo and in vitro. Cell biology and toxicology 21 34331613
2017 A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations. Clinical genetics 21 28386937
2018 Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family. Molecular genetics & genomic medicine 20 29700987
2015 Docosahexaenoic acid inhibits inflammation via free fatty acid receptor FFA4, disruption of TAB2 interaction with TAK1/TAB1 and downregulation of ERK-dependent Egr-1 expression in EA.hy926 cells. Molecular nutrition & food research 20 26577385
2022 Tripartite motif 38 attenuates cardiac fibrosis after myocardial infarction by suppressing TAK1 activation via TAB2/3 degradation. iScience 19 35982795
2021 Circular RNA WHSC1 exerts oncogenic properties by regulating miR-7/TAB2 in lung cancer. Journal of cellular and molecular medicine 19 34551195
2020 A novel TAB2 nonsense mutation (p.S149X) causing autosomal dominant congenital heart defects: a case report of a Chinese family. BMC cardiovascular disorders 19 31959127
2020 Stabilization of the TAK1 adaptor proteins TAB2 and TAB3 is critical for optimal NF-κB activation. The FEBS journal 19 31997570
2024 Regulator of G protein signaling 16 restrains apoptosis in colorectal cancer through disrupting TRAF6-TAB2-TAK1-JNK/p38 MAPK signaling. Cell death & disease 18 38906869
2023 E3 ligase RNF99 negatively regulates TLR-mediated inflammatory immune response via K48-linked ubiquitination of TAB2. Cell death and differentiation 18 36681779
2020 lncRNA CASC2 inhibits lipopolysaccharide‑induced acute lung injury via miR‑27b/TAB2 axis. Molecular medicine reports 18 33174006
2016 Whole Exome Sequencing, Familial Genomic Triangulation, and Systems Biology Converge to Identify a Novel Nonsense Mutation in TAB2-encoded TGF-beta Activated Kinase 1 in a Child with Polyvalvular Syndrome. Congenital heart disease 17 27452334
2013 TAB2, an important upstream adaptor of interleukin-1 signaling pathway, is subject to SUMOylation. Molecular and cellular biochemistry 17 24096733
2022 Inhibition of TAK1/TAB2 complex formation by costunolide attenuates obesity cardiomyopathy via the NF-κB signaling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 16 36332385
2021 gga-miR-142-3p negatively regulates Mycoplasma gallisepticum (HS strain)-induced inflammatory cytokine production via the NF-κB and MAPK signaling by targeting TAB2. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 15 34554275
2023 Tripartite motif 38 alleviates the pathological process of NAFLD-NASH by promoting TAB2 degradation. Journal of lipid research 14 37116711
2020 A single nucleotide deletion resulting in a frameshift in exon 4 of TAB2 is associated with a polyvalular syndrome. European journal of medical genetics 12 31981616
2020 6q25.1 (TAB2) microdeletion is a risk factor for hypoplastic left heart: a case report that expands the phenotype. BMC cardiovascular disorders 12 32183715
2014 TAK1-binding proteins (TAB1 and TAB2) in grass carp (Ctenopharyngodon idella): identification, characterization, and expression analysis after infection with Ichthyophthirius multifiliis. Fish & shellfish immunology 12 24747054
2011 Rhesus monkey TRIM5α represses HIV-1 LTR promoter activity by negatively regulating TAK1/TAB1/TAB2/TAB3-complex-mediated NF-κB activation. Archives of virology 12 21918865
2022 Expanding the phenotype of TAB2 variants and literature review. American journal of medical genetics. Part A 10 35971781
2020 microRNA-128 inhibits the inflammatory responses by targeting TAB2 in miiuy croaker, Miichthysmiiuy. Developmental and comparative immunology 10 33347907
2016 TAK1 adaptor proteins, TAB2 and TAB3, link the signalosome to B-cell receptor-induced IKK activation. FEBS letters 8 27497262
2021 TAB2 Promotes the Stemness and Biological Functions of Cervical Squamous Cell Carcinoma Cells. Stem cells international 7 34306095
2016 A Novel Functional Domain of Tab2 Involved in the Interaction with Estrogen Receptor Alpha in Breast Cancer Cells. PloS one 7 27992601
2007 Expression analysis of the TAB2 protein in adult mouse tissues. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 7 17406806
2021 Structural basis for specific recognition of K6-linked polyubiquitin chains by the TAB2 NZF domain. Biophysical journal 6 34242591
2019 TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis. Human mutation 6 31250519
2024 TAK1-binding protein 2 (TAB2) and TAB3 are redundantly required for TLR-induced cytokine production in macrophages. International immunology 5 38567483
2024 Long non-coding RNA OIP5-AS1 protects neurons from ischemia-reperfusion injury and inhibits neuronal apoptosis through TAB-2. Biochemical and biophysical research communications 5 39693936
2022 A Novel MicroRNA and the Target Gene TAB2 Can Regulate the Process of Sucking Blood in and the Spawn Rate of Hyalomma asiaticum (Acari: Ixodidae) Ticks. Frontiers in immunology 5 35865515
2020 Associations between TAB2 gene polymorphisms and dilated cardiomyopathy in a Chinese population. Biomarkers in medicine 5 32270697
2020 TET2 promotes IL-1β expression in J774.1 cell through TLR4/MAPK signaling pathway with demethylation of TAB2 promoter. Molecular immunology 5 32823238
2019 Associations between TAB2 Gene Polymorphisms and Epithelial Ovarian Cancer in a Chinese Population. Disease markers 5 31485280
2006 Tab2, a novel recombinant polypeptide tag offering sensitive and specific protein detection and reliable affinity purification. Gene 5 16879932
2023 Growth restriction and congenital heart disease caused by a novel TAB2 mutation: A case report. Experimental and therapeutic medicine 4 37153890
2022 TAB2 Promotes the Biological Functions of Head and Neck Squamous Cell Carcinoma Cells via EMT and PI3K Pathway. Disease markers 4 35978886
2025 Lumpy skin disease virus LSDV001 protein positively regulates inflammatory response by promoting assembly of the TAK1-TAB2/3 complex. mBio 3 40852992
2024 The antisense lncRNA of TAB2 that prevents oxidative stress to enhance the follicular growth in mammals. Communications biology 3 39358475
2021 A novel TAB2 mutation detected in a putative case of frontometaphyseal dysplasia. Human genome variation 3 34716296
2006 SUMO4 and MAP3K7IP2 single nucleotide polymorphisms and susceptibility to rheumatoid arthritis. The Journal of rheumatology 3 16755651

Missed literature

Know a paper Affinage missed for TAB2? Flag it for the maintainers and the community.

No submissions yet.