Affinage

TGM2

Protein-glutamine gamma-glutamyltransferase 2 · UniProt P21980

Length
687 aa
Mass
77.3 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TGM2 is a multifunctional enzyme whose Ca²⁺-dependent transamidase, GTP-binding, and protein disulfide isomerase activities operate across distinct subcellular compartments to regulate extracellular matrix homeostasis, cell survival signaling, inflammatory responses, chromatin modification, and autophagy. At the cell surface, TGM2 forms complexes with β1/β3/β5 integrins and syndecan-4 to crosslink extracellular matrix proteins including fibronectin and S100A4, activating FAK- and PKCα-dependent adhesion and survival signaling, while GPR56 opposes this by internalizing and degrading extracellular TGM2 (PMID:16449978, PMID:21046178, PMID:26456735, PMID:24356421). Intracellularly, TGM2 activates NF-κB through either its transamidase or GTP-binding activity depending on cell type, stabilizes STAT1 by blocking TRIM21-mediated ubiquitination via GTP binding, facilitates HSF1 trimerization and nuclear translocation through PDI activity, and coordinates autophagosome–lysosome fusion by binding LC3 through LIR motifs (PMID:19657147, PMID:34485533, PMID:36353796, PMID:29752334, PMID:35913916). In the nucleus, TGM2 catalyzes serotonylation of histone H3 at Q5 in a chromatin accessibility-dependent manner—with TIF1β mediating recruitment to MYC target loci—and interacts with topoisomerase IIα to facilitate DNA double-strand break repair (PMID:36256821, PMID:39788430, PMID:39580966).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2006 High

    Establishing that TGM2 functions as a cell-surface co-receptor by forming complexes with β1/β5 integrins on cancer cells, linking it mechanistically to fibronectin-mediated FAK activation and drug-resistant survival signaling.

    Evidence Co-immunoprecipitation of TGM2–integrin complexes and siRNA knockdown in drug-resistant breast cancer cells

    PMID:16449978

    Open questions at the time
    • Structural basis of TGM2–integrin interaction unknown
    • Whether TGM2 transamidase activity is required for integrin binding was not resolved here
  2. 2006 High

    Identifying GPR56 as an extracellular TGM2-binding partner that suppresses melanoma growth, establishing that TGM2 in the ECM is subject to receptor-mediated regulation rather than acting autonomously.

    Evidence Binding assay and GPR56 overexpression/knockdown in melanoma cells with xenograft validation

    PMID:16757564

    Open questions at the time
    • Mechanism of GPR56-mediated TGM2 clearance not yet defined
    • Whether this applies beyond melanoma was untested
  3. 2009 High

    Demonstrating that TGM2 functions as an intracellular G protein for α1b-adrenergic receptor signaling in hepatocytes, establishing a non-transamidase role in protecting against Fas-mediated apoptosis through Bcl-xL expression.

    Evidence TGM2 knockout mouse model with in vivo and in vitro anti-Fas antibody challenge

    PMID:16108039

    Open questions at the time
    • Whether TGM2's G-protein function extends to other GPCRs beyond adrenergic receptors was unclear
    • Structural basis for GTP hydrolysis by TGM2 not characterized
  4. 2009 High

    Establishing that TGM2 transamidase activity directly drives NF-κB activation and a downstream pro-fibrotic TGFβ1–collagen–fibronectin cascade, and that nitric oxide inactivates this pathway.

    Evidence Inducible TGM2 expression in fibroblasts with site-directed TG inhibitors, NF-κB reporter, TGFβ1 ELISA

    PMID:19657147

    Open questions at the time
    • Direct NF-κB substrate of TGM2 crosslinking not identified
    • Whether nitric oxide modification is at the active-site cysteine or allosteric was not resolved
  5. 2010 High

    Resolving that catalytically active TGM2, but not the Cys277Ser transamidation-deficient mutant, activates TGFβ1 and fibronectin deposition while interacting with β3 integrins, demonstrating that crosslinking activity is essential for ECM remodeling.

    Evidence Stable transfection of wild-type vs. C277S TGM2 mutant, Co-IP of TGM2–β3 integrin complex, functional assays

    PMID:21046178

    Open questions at the time
    • Identity of TGM2's direct crosslinking substrates in the ECM not comprehensively cataloged
  6. 2011 High

    Using active-site mutagenesis in KO-reconstituted cells to prove that transamidase activity is the primary enzymatic function controlling both anti-apoptotic protection and autophagosome formation.

    Evidence TGM2 KO MEF reconstitution with wild-type or C277S mutant, caspase-3/PARP cleavage and LC3-II readouts

    PMID:21479826

    Open questions at the time
    • Molecular targets crosslinked during autophagosome formation not identified
    • Relationship to GTP-binding activity in autophagy regulation not dissected
  7. 2012 Medium

    Identifying PKA-mediated phosphorylation at Ser216 as a regulatory switch required for TGM2-dependent NF-κB activation, Akt activation, and PTEN downregulation, adding a post-translational control layer to TGM2 signaling.

    Evidence S216A mutant reconstitution in TGM2-null MEFs with db-cAMP treatment, NF-κB reporter, Akt/PTEN readouts

    PMID:22759359

    Open questions at the time
    • Whether Ser216 phosphorylation alters TGM2 conformation or protein interactions was not determined
    • Not independently replicated
  8. 2013 High

    Demonstrating that GPR56 clears extracellular TGM2 via internalization and degradation, mechanistically linking GPR56 tumor suppression to removal of TGM2-dependent fibronectin deposition and FAK signaling.

    Evidence Xenograft studies in Tgm2⁻/⁻ mice, internalization/degradation assays

    PMID:24356421

    Open questions at the time
    • Endocytic pathway and degradation compartment for TGM2 not specified
  9. 2013 High

    Establishing S100A4 as both a binding partner and crosslinking substrate of TGM2, with TGM2-mediated S100A4 crosslinking driving cell migration through syndecan-4/α5β1 integrin/PKCα co-signaling.

    Evidence Co-IP, Far Western, in vitro crosslinking, cell-permeable and non-cell-permeable TG2 inhibitors, shRNA knockdown

    PMID:23469180

    Open questions at the time
    • Specific crosslinked S100A4 species identity and stoichiometry not determined
  10. 2015 High

    Showing that TGM2 transamidase activity is required for TGM2 binding to syndecan-4 and its translocation to the extracellular matrix, establishing syndecan-4 as a gatekeeper for extracellular TGM2 function.

    Evidence Cell-permeable fluorescent peptidomimetic TGM2 inhibitor, fibronectin deposition analysis, in vivo nephrosclerosis model

    PMID:26456735

    Open questions at the time
    • Whether syndecan-4 is a direct transamidation substrate or binding partner is not fully resolved
  11. 2016 Medium

    Revealing that TGM2 forms complexes with NF-κB components and drives constitutive NF-κB activation that feeds into IL-6 production and pro-survival autophagy in lymphoma, establishing a TGM2–NF-κB–IL-6–autophagy circuit.

    Evidence CRISPR-mediated TGM2 silencing/overexpression, NF-κB reporter, IL-6 ELISA, autophagy flux, in vivo lymphoma model

    PMID:27488529

    Open questions at the time
    • Direct NF-κB subunit modified or bound by TGM2 not identified
    • ATG5 feedback mechanism on TGM2/NF-κB not mechanistically resolved
  12. 2017 High

    Establishing that TGM2 and Factor XIII-A jointly regulate osteoclastogenesis, RANKL production, and plasma fibronectin assembly into bone, positioning TGM2 as a key transglutaminase in skeletal homeostasis.

    Evidence TGM2/FXIII-A double-KO mice, in vitro osteoclastogenesis, chemical TG inhibition, biomechanical testing

    PMID:28387755

    Open questions at the time
    • Specific TGM2 substrates in bone matrix not identified
    • Individual contributions of TGM2 vs. FXIII-A partially confounded by double KO
  13. 2018 High

    Discovering that TGM2's protein disulfide isomerase activity triggers HSF1 trimerization and nuclear translocation, establishing TGM2 as a proteostasis regulator through a non-transamidase catalytic mechanism.

    Evidence TGM2 KO/KD, nuclear fractionation, HSF1 DNA binding assay, cystic fibrosis mouse model

    PMID:29752334

    Open questions at the time
    • Specific disulfide bonds in HSF1 rearranged by TGM2 not mapped
    • Whether PDI activity operates constitutively or only under stress not defined
  14. 2020 Medium

    Demonstrating that TGM2 promotes mitochondria-associated ER membrane formation under high-glucose conditions by facilitating IP3R1–VDAC1 interactions, linking TGM2 to mitochondrial calcium influx and amyloid beta production in diabetic neurodegeneration.

    Evidence TGM2 siRNA KD, Co-IP of IP3R1–VDAC1, mitochondrial calcium measurement, streptozotocin diabetic mouse model

    PMID:32704090

    Open questions at the time
    • Whether TGM2 directly crosslinks or scaffolds IP3R1–VDAC1 not determined
    • Not independently replicated
  15. 2020 High

    Identifying SERCA2 as a TGM2 serotonylation substrate whose modification under hypoxia inhibits Ca²⁺ reuptake and drives pulmonary vascular smooth muscle proliferation, with vascular smooth muscle-specific Tgm2 KO preventing pulmonary hypertension.

    Evidence Co-IP of serotonylated SERCA2, tissue-specific Tgm2⁻/⁻ mice, intracellular calcium measurement, RVSP/RVHI readouts

    PMID:32116663

    Open questions at the time
    • Specific glutamine residue(s) on SERCA2 modified by TGM2 not identified
    • Serotonin source and regulation in pulmonary vasculature not addressed
  16. 2021 Medium

    Dissecting which enzymatic activity mediates NF-κB activation in microglia: GTP-binding activity, not transamidase activity, is responsible, establishing that TGM2's contribution to NF-κB signaling is cell-type and activity-dependent.

    Evidence Activity-specific TGM2 mutants (GTP-binding vs. transamidase) in LPS-stimulated BV2 and primary microglia

    PMID:34485533

    Open questions at the time
    • Molecular target of TGM2's GTP-binding-dependent NF-κB activation not identified
    • Single lab finding
  17. 2022 High

    Establishing that TGM2 catalyzes histone H3Q5 serotonylation in a chromatin accessibility-dependent manner, with higher-order chromatin structure sterically excluding TGM2 from heterochromatin, defining the epigenetic selectivity principle for this modification.

    Evidence Biochemical reconstitution with purified TGM2 and nucleosome substrates, DNA-barcoded nucleosome libraries, mammalian chromatin profiling

    PMID:36256821

    Open questions at the time
    • Reader proteins recognizing H3Q5ser mark not identified in this study
    • Whether accessibility model extends to other TGM2 histone substrates untested
  18. 2022 High

    Revealing that TGM2 coordinates autophagosome–lysosome fusion after irradiation by binding LC3 through LIR motifs, enabling EPG5 recognition and stabilizing the STX17–SNAP29–VAMP8 SNARE complex, within an SDC1–TGM2–FLOT1–BHMT complex.

    Evidence Co-IP, tandem mass tag proteomics, mRFP-GFP-LC3 flux assay, TEM, LIR mutagenesis, in vivo GBM model

    PMID:35913916 PMID:37441590

    Open questions at the time
    • Whether TGM2 transamidase or GTP-binding activity is required for SNARE complex stabilization not determined
    • Generalizability beyond irradiation stress context unclear
  19. 2022 Medium

    Demonstrating that cytosolic TGM2 stabilizes STAT1 by preventing TRIM21-mediated ubiquitination through its GTP-binding activity, providing a mechanism for TGM2-dependent gastric cancer progression independent of transamidase function.

    Evidence Co-IP, MS identification of TRIM21, GTP-binding mutants, gain/loss-of-function rescue, xenograft models

    PMID:36353796

    Open questions at the time
    • Whether TGM2 directly competes with TRIM21 for STAT1 binding or acts allosterically not resolved
    • Single lab
  20. 2022 High

    Identifying PGE2/PKA signaling as an upstream inducer of Tgm2 expression in lung-resident neutrophils, with Tgm2 deficiency leading to excessive inflammatory cytokine release and exacerbated lung injury, positioning TGM2 as an anti-inflammatory effector in innate immunity.

    Evidence Tgm2 KO mice, BAL fluid treatment, LPS-induced ARDS model, cytokine ELISA

    PMID:35679477

    Open questions at the time
    • TGM2 substrates mediating cytokine suppression in neutrophils not identified
    • Whether transamidase or GTP-binding activity mediates the anti-inflammatory effect not tested
  21. 2024 Medium

    Showing that S-glutathionylation of TGM2 (via GSTP1 upregulation under oxidative stress) triggers its proteasomal degradation and that nuclear TGM2 interacts with topoisomerase IIα to facilitate DNA double-strand break repair, linking TGM2 turnover to DNA repair competence.

    Evidence S-glutathionylation assay, nuclear fractionation, TGM2–TopIIα Co-IP, γ-H2AX foci quantification, xenograft model

    PMID:39580966

    Open questions at the time
    • Mechanism of TGM2–TopIIα cooperation in DNA repair not defined
    • Whether TGM2 crosslinks or scaffolds TopIIα unclear
    • Single lab finding
  22. 2025 High

    Identifying TIF1β as the chromatin recruiter of TGM2 to MYC target gene loci, where TGM2 catalyzes H3Q5 serotonylation to activate MYC pathway transcription in hepatocellular carcinoma, providing the first recruitment mechanism for TGM2's nuclear epigenetic function.

    Evidence CUT&Tag, RNA-seq, liver-specific AAV overexpression, TGM2 inhibitor in HCC organoids and xenografts

    PMID:39788430

    Open questions at the time
    • Whether TIF1β directly binds TGM2 or acts through intermediaries not fully resolved
    • Genome-wide scope of TIF1β-dependent TGM2 recruitment beyond MYC targets unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for TGM2's conformational switch between transamidase-active (open/Ca²⁺-bound) and GTP-binding (closed) states in living cells; the identity of direct crosslinking substrates during autophagosome formation; how TGM2 is selectively directed to different subcellular compartments (nucleus, cell surface, ECM, MAMs); and the full catalog of serotonylation targets beyond H3Q5 and SERCA2.
  • No in-cell structural data on TGM2 conformational dynamics
  • Comprehensive substrate profiling for transamidase and serotonylation activities lacking
  • Mechanism of TGM2 nuclear import undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 6 GO:0003924 GTPase activity 3 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2 GO:0016853 isomerase activity 1
Localization
GO:0005576 extracellular region 4 GO:0005634 nucleus 4 GO:0005886 plasma membrane 4 GO:0005829 cytosol 3 GO:0031012 extracellular matrix 3 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1474244 Extracellular matrix organization 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-4839726 Chromatin organization 2 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1 R-HSA-8953854 Metabolism of RNA 1
Partners
FN1GPR56ITGB1ITGB3LC3S100A4SDC4TOP2A
Complex memberships
SDC1–TGM2–FLOT1–BHMT autophagy complexTGM2–integrin (β1/β3/β5) cell-surface complexTGM2–syndecan-4 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 GPR56 (an adhesion GPCR) binds specifically to tissue transglutaminase TG2 in the extracellular matrix, and this interaction mediates suppression of melanoma tumor growth and metastasis; GPR56 associates in a complex with Gαq and the tetraspanin CD81 Binding assay, overexpression/knockdown in melanoma cells, xenograft tumor models Proceedings of the National Academy of Sciences of the United States of America High 16757564
2013 GPR56 internalizes and degrades extracellular TG2, thereby reducing fibronectin deposition and focal adhesion kinase accumulation; TG2 crosslinking activity promotes melanoma growth, while GPR56 antagonizes this by clearing TG2 Xenograft studies in immunodeficient Tg2−/− mice, internalization/degradation assays, fibronectin deposition analysis Cancer research High 24356421
2006 TG2 associates with β1 and β5 integrins on the cell surface of drug-resistant breast cancer cells and promotes fibronectin-mediated focal adhesion kinase activation, conferring an apoptosis-resistant phenotype; siRNA knockdown of TG2 inhibits fibronectin-mediated cell attachment and survival Co-immunoprecipitation (TG2 with β1/β5 integrins), siRNA knockdown, cell survival assays on fibronectin-coated surfaces Oncogene High 16449978
2009 TG2 acts as a G protein mediating intracellular signaling by the α1b-adrenergic receptor in hepatocytes; TG2 knockout mice show increased hepatocyte sensitivity to Fas-mediated apoptosis due to impaired adrenergic signaling and decreased Bcl-xL expression TG2 knockout mouse model, in vivo and in vitro anti-Fas antibody treatment, Bcl-xL expression analysis Hepatology (Baltimore, Md.) High 16108039
2009 TG2 transamidating/crosslinking activity stimulates NF-κB activation in fibroblasts, leading to increased TGFβ1 expression and secretion, which in turn elevates collagen and fibronectin synthesis and deposition; nitric oxide suppresses TG2 activity and reverses this pro-fibrotic cascade Tetracycline-inducible TG2 expression system in Swiss 3T3 fibroblasts, site-directed TG inhibitors, NF-κB reporter assay, TGFβ1 ELISA The Journal of biological chemistry High 19657147
2011 TG2 transamidating activity is the primary biochemical function regulating both apoptosis and autophagy; the transamidation-inactive C277S mutant fails to suppress caspase-3/PARP cleavage during apoptosis and fails to catalyze final steps of autophagosome formation TG2 knockout MEF reconstitution with wild-type or C277S transamidation-inactive mutant, apoptosis and autophagy induction assays, LC3-II immunoblot Amino acids High 21479826
2010 TG2 directly interacts with β3 integrins on the cell surface (confirmed by immunoprecipitation), acting as a co-receptor for fibronectin; catalytically active TG2 (but not the transamidation-inactive Cys277Ser mutant) activates TGFβ1 and increases fibronectin deposition, enhancing cell adhesion and reducing migration Stable transfection of CT26 cells with wild-type or Cys277Ser TG2, immunoprecipitation of TG2–β3 integrin complex, TGFβ1 measurement, migration assays, site-directed TG inhibitors Amino acids High 21046178
2013 TG2 directly binds and crosslinks S100A4, and acts as a substrate enzyme for S100A4 (confirmed by Co-IP, Far Western blotting, and crosslinking assays); TG2-mediated S100A4 crosslinking promotes cell migration through syndecan-4 and α5β1 integrin co-signaling pathways linked by PKCα activation Co-immunoprecipitation, Far Western blotting, in vitro crosslinking assay, shRNA knockdown, TG2-specific inhibitors (cell-permeable and non-cell-permeable), functional blocking antibodies PloS one High 23469180
2015 TG2 binds cell surface syndecan-4; inhibition of TG2 transamidating activity by a cell-permeable fluorescent inhibitor blocks TG2 binding to syndecan-4, inhibits TG2 translocation into the extracellular matrix, and reduces fibronectin deposition, cell motility, and cord formation in endothelial cells Cell-permeable fluorescently labeled peptidomimetic TG2 inhibitor, in situ TG2 activity assay, fibronectin deposition analysis, cell motility assays, Matrigel cord formation, mouse model of nephrosclerosis Chemistry & biology High 26456735
2012 PKA-induced phosphorylation of TG2 at serine-216 is required for TG2-mediated NF-κB activation, Akt activation, and PTEN downregulation; a TG2 mutant lacking the Ser216 phosphorylation site (m-TG2) fails to activate NF-κB, fails to promote Akt phosphorylation, and fails to downregulate PTEN TG2 null MEF reconstitution with wild-type or S216A TG2, db-cAMP (PKA activator) treatment, NF-κB reporter assay, Akt immunoblot, PTEN mRNA and protein quantification, MCF-7/T-47D validation BMC cancer Medium 22759359
2018 TG2, via its protein disulfide isomerase (PDI) activity, triggers trimerization and nuclear translocation of HSF1 and enables HSF1 DNA binding to the HSP70 promoter; TG2 loss impairs HSF1 nuclear translocation and HSP70 induction during proteotoxic stress TG2 loss-of-function (KO/KD), nuclear fractionation, HSF1 DNA binding assay (ChIP/EMSA), cystic fibrosis mouse model lacking TG2, CFTR functional measurement EMBO reports High 29752334
2022 TGM2 installs serotonin onto glutamine-5 of histone H3 (H3Q5ser) via its transamidase activity; histone serotonylation by TGM2 is excluded from constitutive heterochromatic regions because higher-order chromatin structures impose a steric barrier to TGM2 activity, and accessibility rather than primary sequence or pre-existing PTMs dictates TGM2 substrate selectivity at chromatin Biochemical reconstitution with purified TGM2 and nucleosome substrates, DNA-barcoded nucleosome libraries, structure-activity relationship studies, mammalian cell chromatin localization (histone mark profiling) Proceedings of the National Academy of Sciences of the United States of America High 36256821
2020 TGM2 promotes formation of mitochondria-associated ER membranes (MAMs) under high-glucose conditions; TGM2 silencing inhibits IP3R1–VDAC1 interactions, preventing mitochondrial calcium influx, mitochondrial ROS accumulation, and amyloid beta production in neuronal cells TGM2 siRNA knockdown, Co-IP of IP3R1–VDAC1, mitochondrial calcium measurement (Fluo-4AM), mtROS quantification, streptozotocin diabetic mouse model Cell death and differentiation Medium 32704090
2020 TG2 mediates serotonylation of SERCA2 (sarco-endoplasmic reticulum Ca2+ ATPase) under hypoxic conditions; TG2-mediated SERCA2 serotonylation inhibits SERCA2 activity, increases cytosolic Ca2+ via TRPC6-dependent store-operated calcium entry, and promotes pulmonary vascular smooth muscle cell proliferation; vascular smooth muscle-specific TG2 knockout prevents hypoxic pulmonary hypertension in mice Co-immunoprecipitation of serotonylated SERCA2, TG2 overexpression/silencing, Fluo-4AM intracellular calcium measurement, vascular smooth muscle-specific Tgm2−/− mouse model, RVSP/RVHI measurement Frontiers in pharmacology High 32116663
2016 TG2 forms complexes with NF-κB components and drives constitutive NF-κB activation; under stress, TG2 and NF-κB induce IL-6 production, which in turn activates autophagy to promote mantle cell lymphoma cell survival; ATG5 positively feeds back on the TG2/NF-κB/IL-6 axis CRISPR-mediated TG2 silencing, TG2 overexpression, autophagy flux assays, IL-6 ELISA, NF-κB reporter, ATG5 modulation, in vivo lymphoma models Cancer research Medium 27488529
2022 After irradiation, TGM2 is transported from the cell membrane to lysosomes by SDC1, and then TGM2 binds LC3 through two LC3-interacting regions (LIRs), coordinating autophagosome-lysosome fusion by enabling EPG5 recognition of LC3 and stabilizing the STX17-SNAP29-VAMP8 SNARE complex; SDC1-TGM2-FLOT1-BHMT form a complex that maintains autophagic flux in irradiated GBM cells Co-immunoprecipitation, tandem mass tag proteomic analysis, mRFP-GFP-LC3 autophagy flux assay, immunofluorescence, transmission electron microscopy, LIR mutagenesis (implied), in vivo GBM mouse model Autophagy / Theranostics High 35913916 37441590
2022 Cytosolic TGM2 promotes gastric cancer progression through its GTP-binding enzymatic activity by facilitating dissociation of the ubiquitin E3 ligase TRIM21 from STAT1, thereby preventing TRIM21-mediated ubiquitination and degradation of STAT1 and maintaining STAT1 protein stability Co-immunoprecipitation, mass spectrometry identification of TRIM21 as STAT1 E3 ligase, TGM2 GTP-binding mutants, gain/loss-of-function rescue experiments, xenograft and metastasis models, A23187 (Ca2+ ionophore) to modulate TGM2 activity Cancer communications (London, England) Medium 36353796
2016 IL-1β induces IL-6 production in TG2-expressing breast cancer cells through NF-κB-, PI3K-, and JNK-dependent mechanisms; TG2 expression is required for this IL-1β-driven IL-6 induction and the resulting increase in invasiveness and estrogen-independent tumor growth Stable TG2 transfection in MCF7 cells, cytokine stimulation, anti-IL-6/anti-IL-1β antibody neutralization, 3D culture and in vivo mammary fat pad xenograft BMC cancer Medium 27609180
2016 PARP3 promotes TGFβ- and ROS-induced EMT by stimulating a TG2-Snail-E-cadherin axis; PARP3 depletion prevents TGFβ-dependent TG2 induction and downstream Snail upregulation/E-cadherin downregulation PARP3 siRNA depletion, TGFβ treatment, Western blot for TG2/Snail/E-cadherin, migration and chemoresistance assays, stem cell marker analysis Oncotarget Medium 27579892
2007 Missense mutations in TGM2 located close to the catalytic site (M330R, I331N, N333S) impair transamidating activity in vitro and are associated with early-onset type 2 diabetes; TG2 is the only transglutaminase significantly expressed in human pancreatic islet cells TGM2 gene sequencing in MODY/early-onset T2D patients, in vitro transamidation activity assay of mutant proteins, gene expression analysis of TGM family in pancreatic tissue Human mutation Medium 17939176
2017 TG2 and Factor XIII-A control monocyte-macrophage differentiation into osteoclasts, regulate RANKL production in mesenchymal stem cells and adipocytes, and are required for plasma fibronectin assembly into bone; TG2/FXIII-A double-KO mice show increased osteoclastogenesis, increased bone marrow adipogenesis, and plasma FN retention TG2/FXIII-A knockout mice, in vitro osteoclastogenesis assay, chemical TG activity inhibition, RANKL/OPG expression, biomechanical bone testing, plasma FN assembly assay Cell death and differentiation High 28387755
2025 TGM2-mediated serotonylation of glutamine-5 on histone H3 (H3Q5ser) promotes HCC progression; transcriptional intermediary factor 1β (TIF1β) mediates recruitment of TGM2 to MYC target gene loci, facilitating H3Q5ser modification and activating MYC pathway transcription CUT&Tag and RNA sequencing, adeno-associated virus liver-specific TGM2/H3.3 overexpression, TGM2 inhibitor treatment in HCC organoids and xenograft models, hydrodynamic tail vein injection model Journal of hepatology High 39788430
2022 Weakly migratory breast cancer cells release TG2-enriched microvesicles that activate fibroblasts, leading fibroblast-directed cancer cell migration; microvesicle-TG2 induces tumor stiffening and fibroblast activation in vivo and enhances metastasis of weakly migratory cells Phenotypic cell sorting, microvesicle isolation and proteomic characterization, in vitro migration assays, in vivo tumor stiffening and metastasis models eLife Medium 36475545
2021 TGM2 promotes NF-κB p65 nuclear translocation, which transcriptionally activates fibronectin 1 (FN1); the NEAT1_2 lncRNA sponges miR-491 to regulate TGM2 expression, and TGM2–NFκB–FN1 signaling promotes papillary thyroid cancer invasion and metastasis TGM2 siRNA knockdown, NF-κB p65 nuclear fractionation, dual-luciferase reporter assay (miR-491 binding to NEAT1_2 and TGM2 3'UTR), Transwell and wound healing assays, lung metastasis mouse model Frontiers in oncology Medium 33738254
2022 In lung-resident neutrophils, prostaglandin E2 (PGE2) acts via protein kinase A (PKA) to induce Tgm2 expression; Tgm2-deficient neutrophils release excessive inflammatory cytokines upon LPS stimulation, and Tgm2−/− mice show exacerbated lung damage in an LPS-induced ARDS model Tgm2 knockout mice, bronchoalveolar lavage fluid treatment of bone marrow neutrophils, LPS challenge, cytokine ELISA, ARDS model Blood High 35679477
2020 Blocking TG2 attenuates bleomycin-induced pulmonary fibrosis by inhibiting EMT; TG2 KD or inhibition suppresses Akt activation, and Akt reactivation (by SC79) rescues the EMT inhibition caused by TG2 knockdown, placing TG2 upstream of Akt in EMT regulation siRNA knockdown of TG2 in MLE12 alveolar epithelial cells, GK921 TG2 inhibitor, SC79 (Akt activator) rescue experiment, bleomycin mouse model, Western blot for EMT markers Respiratory physiology & neurobiology Medium 32006666
2021 TGM2 promotes NF-κB signaling in microglia via its GTP-binding activity (not transamidase activity); gain-of-function with transamidase-deficient TGM2 still activates NF-κB and microglial inflammation, whereas GTP-binding-deficient mutant does not TGM2 siRNA knockdown, gain-of-function with GTP-binding vs. transamidase activity mutants, NF-κB signaling assay, LPS-stimulated BV2 and primary microglia Journal of immunology research Medium 34485533
2020 AFF1 binds to the promoter region of the Tgm2 gene and directly regulates its transcription; AFF1 inhibition of adipogenic differentiation in mesenchymal stem cells is rescued by Tgm2 overexpression, placing TGM2 downstream of AFF1 in adipogenic regulation ChIP-qPCR (AFF1 at Tgm2 promoter), RNA-seq, AFF1 siRNA/overexpression, Tgm2 overexpression rescue, Oil Red O staining, in vivo adipose formation Cell proliferation Medium 32441391
2024 RSL3-induced oxidative stress promotes S-glutathionylation of TGM2 via upregulation of GSTP1, leading to proteasomal degradation of TGM2; TGM2 normally accumulates in the nucleus after irradiation and interacts with topoisomerase IIα to facilitate DNA repair; loss of TGM2 through this mechanism impairs DNA DSB repair and inhibits EMT TGM2 overexpression/knockdown, S-glutathionylation assay, nuclear fractionation, TGM2–topoisomerase IIα Co-IP, γ-H2AX foci for DSB quantification, ferroptosis inhibitor controls, xenograft model Redox biology Medium 39580966

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America 225 16757564
2011 Extracellular TG2: emerging functions and regulation. The FEBS journal 164 21902810
2020 Urolithin A suppresses high glucose-induced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium homeostasis. Cell death and differentiation 140 32704090
2021 Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling. BMC cancer 125 33845796
2006 Implications of increased tissue transglutaminase (TG2) expression in drug-resistant breast cancer (MCF-7) cells. Oncogene 122 16449978
2006 Tissue transglutaminase (TG2)--a wound response enzyme. Frontiers in bioscience : a journal and virtual library 101 16146777
2019 MiR-532-3p suppresses colorectal cancer progression by disrupting the ETS1/TGM2 axis-mediated Wnt/β-catenin signaling. Cell death & disease 97 31570702
2011 TG2, a novel extracellular protein with multiple functions. Amino acids 97 21818567
2020 Tunable bioactivity and mechanics of collagen-based tissue engineering constructs: A comparison of EDC-NHS, genipin and TG2 crosslinkers. Biomaterials 91 32480093
2016 IL-1β induces IL-6 production and increases invasiveness and estrogen-independent growth in a TG2-dependent manner in human breast cancer cells. BMC cancer 87 27609180
2018 Nicotine induces apoptosis in human osteoblasts via a novel mechanism driven by H2O2 and entailing Glyoxalase 1-dependent MG-H1 accumulation leading to TG2-mediated NF-kB desensitization: Implication for smokers-related osteoporosis. Free radical biology & medicine 84 29355739
2008 The transglutaminase 2 gene (TGM2), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer. Carcinogenesis 82 18174247
2000 Simultaneous estimation of T(G2+M), T(S), and T(pot) using single sample dynamic tumor data from bivariate DNA-thymidine analogue cytometry. Cytometry 77 10942890
2016 PARP3 controls TGFβ and ROS driven epithelial-to-mesenchymal transition and stemness by stimulating a TG2-Snail-E-cadherin axis. Oncotarget 71 27579892
2009 Increased TG2 expression can result in induction of transforming growth factor beta1, causing increased synthesis and deposition of matrix proteins, which can be regulated by nitric oxide. The Journal of biological chemistry 70 19657147
2014 Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion. Journal of cellular and molecular medicine 68 25215932
2010 A profiling platform for the characterization of transglutaminase 2 (TG2) inhibitors. Journal of biomolecular screening 67 20395409
2013 TGM2 and implications for human disease: role of alternative splicing. Frontiers in bioscience (Landmark edition) 59 23276939
2013 GPR56 inhibits melanoma growth by internalizing and degrading its ligand TG2. Cancer research 59 24356421
2022 Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21-mediated ubiquitination/degradation of STAT1 in a GTP binding-dependent modality. Cancer communications (London, England) 56 36353796
2013 TGM2 inhibition attenuates ID1 expression in CD44-high glioma-initiating cells. Neuro-oncology 56 23877317
2022 SDC1-dependent TGM2 determines radiosensitivity in glioblastoma by coordinating EPG5-mediated fusion of autophagosomes with lysosomes. Autophagy 52 35913916
2016 TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy. Cancer research 51 27488529
2017 Tampering with cancer chemoresistance by targeting the TGM2-IL6-autophagy regulatory network. Autophagy 48 28056186
2015 Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions. Chemistry & biology 45 26456735
2019 TGM2 interference regulates the angiogenesis and apoptosis of colorectal cancer via Wnt/β-catenin pathway. Cell cycle (Georgetown, Tex.) 44 31010374
2023 Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation. Journal for immunotherapy of cancer 43 36639156
2007 GPR56 and TG2: possible roles in suppression of tumor growth by the microenvironment. Cell cycle (Georgetown, Tex.) 43 17314516
2005 Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice. Hepatology (Baltimore, Md.) 43 16108039
2016 Role of tissue transglutaminase-2 (TG2)-mediated aminylation in biological processes. Amino acids 42 27270573
2013 Up-regulation of TGM2 with ITGB1 and SDC4 is important in the development and metastasis of renal cell carcinoma. Urologic oncology 42 23499501
2011 TG2 transamidating activity acts as a reostat controlling the interplay between apoptosis and autophagy. Amino acids 42 21479826
2013 The role of TG2 in regulating S100A4-mediated mammary tumour cell migration. PloS one 41 23469180
2015 Silencing of TGM2 reverses epithelial to mesenchymal transition and modulates the chemosensitivity of breast cancer to docetaxel. Experimental and therapeutic medicine 40 26622499
2018 TG2 regulates the heat-shock response by the post-translational modification of HSF1. EMBO reports 39 29752334
2017 Transglutaminases factor XIII-A and TG2 regulate resorption, adipogenesis and plasma fibronectin homeostasis in bone and bone marrow. Cell death and differentiation 39 28387755
2008 Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocrine-related cancer 38 18794325
2011 Recent advances in the development of tissue transglutaminase (TG2) inhibitors. Amino acids 37 22160259
2021 The NEAT1_2/miR-491 Axis Modulates Papillary Thyroid Cancer Invasion and Metastasis Through TGM2/NFκb/FN1 Signaling. Frontiers in oncology 35 33738254
2007 Missense mutations in the TGM2 gene encoding transglutaminase 2 are found in patients with early-onset type 2 diabetes. Mutation in brief no. 982. Online. Human mutation 34 17939176
2022 Unique characteristics of lung-resident neutrophils are maintained by PGE2/PKA/Tgm2-mediated signaling. Blood 33 35679477
2021 N6-methyladenosine modification of TGM2 mRNA contributes to the inhibitory activity of sarsasapogenin in rheumatoid arthritis fibroblast-like synoviocytes. Phytomedicine : international journal of phytotherapy and phytopharmacology 33 34902811
2023 SDC1-TGM2-FLOT1-BHMT complex determines radiosensitivity of glioblastoma by influencing the fusion of autophagosomes with lysosomes. Theranostics 32 37441590
2017 TGC repeat expansion in the TCF4 gene increases the risk of Fuchs' endothelial corneal dystrophy in Australian cases. PloS one 32 28832669
2018 TGM2 knockdown reverses cisplatin chemoresistance in osteosarcoma. International journal of molecular medicine 30 30015899
2022 TGM2-mediated histone transglutamination is dictated by steric accessibility. Proceedings of the National Academy of Sciences of the United States of America 28 36256821
2021 Circular RNA circ_0081001 knockdown enhances methotrexate sensitivity in osteosarcoma cells by regulating miR-494-3p/TGM2 axis. Journal of orthopaedic surgery and research 28 33435987
2012 Phosphorylation of transglutaminase 2 (TG2) at serine-216 has a role in TG2 mediated activation of nuclear factor-kappa B and in the downregulation of PTEN. BMC cancer 28 22759359
2023 Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer. Cellular oncology (Dordrecht, Netherlands) 27 37246171
2019 CD44, TGM2 and EpCAM as novel plasma markers in endometrial cancer diagnosis. BMC cancer 26 31035965
2012 Tissue transglutaminase (TG-2) modified amniotic membrane: a novel scaffold for biomedical applications. Biomedical materials (Bristol, England) 26 22652528
2020 Role of TG2-Mediated SERCA2 Serotonylation on Hypoxic Pulmonary Vein Remodeling. Frontiers in pharmacology 25 32116663
2016 Association of TG2 from mast cells and chronic spontaneous urticaria pathogenesis. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 24 27613463
2014 TGM2: a cell surface marker in esophageal adenocarcinomas. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 24 24828664
2013 Electrochemical magneto immunosensor for the detection of anti-TG2 antibody in celiac disease. Biosensors & bioelectronics 22 23685317
2008 FXIIIA and TGF-beta over-expression produces normal musculo-skeletal phenotype in TG2-/- mice. Amino acids 22 18594942
1995 Band 4.2 Shiga: 317 CGC-->TGC in compound heterozygotes with 142 GCT-->ACT results in band 4.2 deficiency and microspherocytosis. British journal of haematology 22 8547071
2010 The role of tissue transglutaminase (TG2) in regulating the tumour progression of the mouse colon carcinoma CT26. Amino acids 21 21046178
2023 TG2 promotes amyloid beta aggregates: Impact on ER-mitochondria crosstalk, calcium homeostasis and synaptic function in Alzheimer's disease. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 36989728
2013 Celiac Disease-Specific TG2-Targeted Autoantibodies Inhibit Angiogenesis Ex Vivo and In Vivo in Mice by Interfering with Endothelial Cell Dynamics. PloS one 20 23824706
2011 Tissue Transglutaminase (TG2)-Induced Inflammation in Initiation, Progression, and Pathogenesis of Pancreatic Cancer. Cancers 20 24212645
2021 Propofol Suppresses Microglia Inflammation by Targeting TGM2/NF-κB Signaling. Journal of immunology research 19 34485533
2020 Blocking TG2 attenuates bleomycin-induced pulmonary fibrosis in mice through inhibiting EMT. Respiratory physiology & neurobiology 19 32006666
2017 Tissue transglutaminase (TG2) and mitochondrial function and dysfunction. Frontiers in bioscience (Landmark edition) 19 28199195
2008 Homocysteine-induced toxicity increases TG2 expression in Neuro2a cells. Amino acids 18 18594946
1999 Fibrinogen Matsumoto III: a variant with gamma275 Arg-->Cys (CGC-->TGC)--comparison of fibrin polymerization properties with those of Matsumoto I (gamma364 Asp-->His) and Matsumoto II (gamma308 Asn-->Lys). Thrombosis and haemostasis 18 10365751
2017 Purification and Characterization of Bacteriocin Produced by a Strain of Enterococcus faecalis TG2. Applied biochemistry and biotechnology 17 28952066
2006 Two novel Italian CADASIL families from Central Italy with mutation CGC-TGC at codon 1006 in the exon 19 Notch3 gene. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 17 16998728
1997 Sequence-specific local structural variations in solution structures of d(CGXX'CG)2 and d(CAXX'TG)2 self-complementary deoxyribonucleic acids. Journal of molecular biology 17 9102467
2023 TGM2, HMGA2, FXYD3, and LGALS4 genes as biomarkers in acquired oxaliplatin resistance of human colorectal cancer: A systems biology approach. PloS one 16 37535601
2022 Implications of enigmatic transglutaminase 2 (TG2) in cardiac diseases and therapeutic developments. Biochemical pharmacology 16 35617996
2022 RSL3 triggers glioma stem cell differentiation via the Tgm2/AKT/ID1 signaling axis. Biochimica et biophysica acta. Molecular basis of disease 16 36041715
2020 Enhanced neural differentiation of neural stem cells by sustained release of Shh from TG2 gene-modified EMSC co-culture in vitro. Amino acids 16 33245424
2019 Overexpression of TG2 enhances the differentiation of ectomesenchymal stem cells into neuron‑like cells and promotes functional recovery in adult rats following spinal cord injury. Molecular medicine reports 16 31322240
2017 Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia. Cell death & disease 16 28151477
2022 Weakly migratory metastatic breast cancer cells activate fibroblasts via microvesicle-Tg2 to facilitate dissemination and metastasis. eLife 15 36475545
2021 High-risk endometrial cancer proteomic profiling reveals that FBXW7 mutation alters L1CAM and TGM2 protein levels. Cancer 15 33872388
2020 Intestinal TG3- and TG2-Specific Plasma Cell Responses in Dermatitis Herpetiformis Patients Undergoing a Gluten Challenge. Nutrients 15 32069794
2025 TGM2-mediated histone serotonylation promotes HCC progression via MYC signalling pathway. Journal of hepatology 14 39788430
2023 18β-glycyrrhetinic acid inhibits proliferation of gastric cancer cells through regulating the miR-345-5p/TGM2 signaling pathway. World journal of gastroenterology 14 37398884
2021 TG2-gluten complexes as antigens for gluten-specific and transglutaminase-2 specific B cells in celiac disease. PloS one 14 34731200
2022 Role of TGM2 in T‑cell lymphoblastic lymphoma via regulation of IL‑6/JAK/STAT3 signalling. Molecular medicine reports 13 35014680
2021 ETS1 Ameliorates Hyperoxia-Induced Alveolar Epithelial Cell Injury by Regulating the TGM2-Mediated Wnt/β-Catenin Pathway. Lung 13 34817668
2012 The role of TG2 in ECV304-related vasculogenic mimicry. Amino acids 13 22231926
2010 TG2 protects neuroblastoma cells against DNA-damage-induced stress, suppresses p53 activation. Amino acids 13 20112034
2020 AFF1 inhibits adipogenic differentiation via targeting TGM2 transcription. Cell proliferation 12 32441391
2020 Vitamin D Status Modulates Inflammatory Response in HIV+ Subjects: Evidence for Involvement of Autophagy and TG2 Expression in PBMC. International journal of molecular sciences 12 33066266
2019 Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs. Clinical science (London, England : 1979) 12 31830262
2009 The TGM2 gene is associated with schizophrenia in a British population. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 12 18561261
2024 RSL3 sensitizes glioma cells to ionizing radiation by suppressing TGM2-dependent DNA damage repair and epithelial-mesenchymal transition. Redox biology 11 39580966
2023 TGM2 accelerates migration and differentiation of BMSCs by activating Wnt/β-catenin signaling. Journal of orthopaedic surgery and research 11 36872331
2016 Characterization of TG2 and TG1-TG2 double knock-out mouse epidermis. Amino acids 11 27864691
2015 [TGC Repeats in Intron 2 of the TCF4 Gene have a Good Predictive Power Regarding to Fuchs Endothelial Corneal Dystrophy]. Klinische Monatsblatter fur Augenheilkunde 11 26280645
2015 Mechanism of BMP and TG2 in mesenchymal stem cell osteogenesis. European review for medical and pharmacological sciences 11 26636505
2009 Effect of transglutaminase 2 (TG2) deficiency on atherosclerotic plaque stability in the apolipoprotein E deficient mouse. Atherosclerosis 11 20003977
2023 Dioscin Impedes Proliferation, Metastasis and Enhances Autophagy of Gastric Cancer Cells via Regulating the USP8/TGM2 Pathway. Molecular biotechnology 10 38085503
2022 Urinary levels of pro-fibrotic transglutaminase 2 (TG2) may help predict progression of chronic kidney disease. PloS one 10 35041708
2020 Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31-43 and Anti-TG2 Antibodies in Celiac Disease. International journal of molecular sciences 10 32456177
2018 Small-intestinal TG2-specific plasma cells at different stages of coeliac disease. BMC immunology 10 30522434
2016 P2X7 receptor-mediated TG2 externalization: a link to inflammatory arthritis? Amino acids 10 27562793