Affinage

TGM2

Protein-glutamine gamma-glutamyltransferase 2 · UniProt P21980

Length
687 aa
Mass
77.3 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TGM2 is a multifunctional enzyme whose distinct biochemical activities—Ca²⁺-dependent transamidation, GTP-binding, and protein disulfide isomerase (PDI) activity—drive context-specific control of extracellular matrix assembly, cell survival, autophagy, and transcription (PMID:21479826, PMID:29752334, PMID:36353796). Its transamidase activity, dependent on the active-site cysteine (mutated in C277S), is the primary function required for protection from apoptosis and for autophagosome formation, crosslinks matrix proteins, and polymerizes substrates such as S100A4 to promote tumor cell migration (PMID:21479826, PMID:23469180, PMID:20112034). At the cell surface TGM2 acts as a fibronectin co-receptor in complexes with β1/β3/β5 integrins and syndecan-4, activating focal adhesion kinase and PKCα to drive fibronectin-mediated adhesion and survival signaling (PMID:16449978, PMID:23469180, PMID:21046178), and it promotes a feed-forward fibrotic program by activating NF-κB to upregulate TGFβ1 and increase collagen/fibronectin deposition (PMID:19657147, PMID:26456735). Through monoaminylation chemistry TGM2 serotonylates SERCA2 to inhibit calcium reuptake in hypoxic pulmonary smooth muscle and installs H3Q5 serotonylation on chromatin, with substrate accessibility rather than sequence determining nucleosomal targeting, and TIF1β recruiting TGM2 to MYC target loci to activate transcription (PMID:36256821, PMID:32116663, PMID:39788430). Independently of transamidation, TGM2's GTP-binding activity activates NF-κB and stabilizes STAT1 by displacing it from the TRIM21 E3 ligase, while its PDI activity triggers HSF1 trimerization and the heat-shock response (PMID:29752334, PMID:36353796, PMID:34485533). TGM2 activity and localization are tuned by post-translational modifications—PKA phosphorylation at Ser216 enables NF-κB/Akt pro-survival signaling, Fyn phosphorylation at Tyr369 regulates autophagy, and S-glutathionylation triggers its degradation (PMID:22759359, PMID:37190106, PMID:39580966). Genetically, TGM2 catalytic-site missense mutations impair transamidation and Tgm2-deficient mice are glucose-intolerant with impaired insulin secretion, linking the enzyme to islet function (PMID:17939176).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2005 High

    Established that TGM2 functions as a G protein in receptor signaling distinct from its crosslinking role, controlling apoptotic threshold via Bcl-xL.

    Evidence Tgm2 knockout mice challenged with anti-Fas, with Bcl-xL/FLIP immunoblotting and α1b-adrenergic receptor analysis in hepatocytes

    PMID:16108039

    Open questions at the time
    • Did not resolve which TGM2 enzymatic activity (GTP-binding vs transamidase) mediates the adrenergic signaling
    • Mechanism of Bcl-xL transcriptional control left undefined
  2. 2006 High

    Defined TGM2's cell-surface role as an integrin co-receptor that activates FAK to drive fibronectin adhesion and survival, and identified GPR56 as a binding partner that suppresses tumor growth.

    Evidence Co-IP of TG2–integrin and TG2–GPR56 complexes, siRNA knockdown, fibronectin attachment/FAK assays, xenograft models

    PMID:16449978 PMID:16757564

    Open questions at the time
    • Whether integrin binding requires catalytic activity not addressed
    • Structural basis of TG2–GPR56 interaction unknown
  3. 2009 High

    Showed that TGM2 transamidase activity drives a profibrotic program by activating NF-κB and inducing TGFβ1, connecting the enzyme to matrix synthesis.

    Evidence Tetracycline-inducible TG2 in fibroblasts, site-directed TG inhibitor, NF-κB reporter, NO donor treatment

    PMID:19657147

    Open questions at the time
    • Direct crosslinking substrate triggering NF-κB not identified
    • How NO arrests enzyme on cell surface mechanistically unclear
  4. 2010 Medium

    Used active-site mutants to prove transamidase activity is required for TGM2's anti-apoptotic function and to confirm β3-integrin co-receptor activity raises matrix fibronectin.

    Evidence WT vs C277S TG2 in neuroblastoma and colon carcinoma cells, caspase-3/p53 assays, TG2–β3 co-IP, fibronectin deposition

    PMID:20112034 PMID:21046178

    Open questions at the time
    • Survival substrate of transamidation not identified
    • Single-lab findings for each cell context
  5. 2011 High

    Pinpointed transamidation as the single activity required for both apoptosis protection and autophagosome formation using knockout reconstitution.

    Evidence TG2-null MEF reconstituted with WT or C277S, caspase-3/PARP cleavage and LC3-II immunoblotting

    PMID:21479826

    Open questions at the time
    • Molecular crosslinking targets governing autophagy unresolved
    • Subcellular site of relevant activity not localized
  6. 2012 Medium

    Identified PKA-mediated Ser216 phosphorylation as a switch enabling TGM2's pro-survival NF-κB/Akt/PTEN signaling.

    Evidence TG2-null MEF reconstituted with WT or Ser216A mutant, NF-κB reporter, immunoblotting, validated in two breast cancer lines

    PMID:22759359

    Open questions at the time
    • Whether Ser216 phosphorylation alters enzymatic activity unclear
    • Single lab
  7. 2013 High

    Established that TGM2 polymerizes S100A4 to promote migration, that the GPR56 antagonism proceeds via TG2 internalization/degradation, and that extracellular TG2 activity supports vasculogenic tube formation.

    Evidence Crosslinking/Far-Western/co-IP for S100A4, Tg2-/- xenografts for GPR56, cell-permeable vs non-permeable inhibitors for tube formation

    PMID:22231926 PMID:23469180 PMID:24356421

    Open questions at the time
    • Syndecan-4/PKCα signaling steps downstream of S100A4 incompletely mapped
    • Identity of physiological extracellular substrates in tubes partial
  8. 2016 Medium

    Distinguished GTP-binding from transamidase activity in inflammatory signaling and embedded TGM2 in NF-κB/IL-6/autophagy survival loops and TGFβ-driven EMT axes.

    Evidence Activity-specific mutants in microglia, CRISPR silencing/co-IP with NF-κB in lymphoma, PARP3 depletion in EMT models, syndecan-4-targeted inhibitor

    PMID:26456735 PMID:27488529 PMID:27579892 PMID:34485533

    Open questions at the time
    • Direct TG2–PARP3 binding not shown
    • GTP-binding effector linking to NF-κB not defined
  9. 2018 High

    Assigned a PDI-dependent function to TGM2 in triggering HSF1 trimerization and the heat-shock response, with disease relevance in cystic fibrosis.

    Evidence TG2 knockout CF mice, HSF1 nuclear translocation/DNA-binding assays, CFTR functional measurement

    PMID:29752334

    Open questions at the time
    • Direct disulfide substrate on HSF1 not identified
    • How PDI activity is regulated in cells unclear
  10. 2020 High

    Defined serotonylation as a TGM2 catalytic output controlling calcium handling, modifying SERCA2 in hypoxic pulmonary smooth muscle and tethering ER–mitochondria membranes for calcium influx.

    Evidence TG2–SERCA2 and IP3R1–VDAC1 co-IPs, calcium/mtROS imaging, smooth-muscle-specific Tgm2-/- and STZ diabetic mouse models

    PMID:32116663 PMID:32704090

    Open questions at the time
    • Whether MAM tethering involves crosslinking of specific substrates unresolved
    • HIF-2 to TG2 transcriptional link mechanism partial
  11. 2022 High

    Revealed TGM2 GTP-binding stabilizes STAT1 by displacing TRIM21, defined SDC1-dependent lysosomal trafficking that couples TGM2 to autophagosome–lysosome fusion, and showed chromatin accessibility governs histone serotonylation.

    Evidence GTP-binding mutants/ubiquitination assays for STAT1, LIR-mutation and SNARE-complex analysis for SDC1-TGM2-LC3, DNA-barcoded nucleosome libraries for H3Q5ser, microvesicle TG2 cargo assays

    PMID:35679477 PMID:35913916 PMID:36256821 PMID:36353796 PMID:36475545

    Open questions at the time
    • How GTP-binding promotes TRIM21–STAT1 dissociation structurally unknown
    • Signal triggering SDC1-mediated TGM2 internalization beyond irradiation unclear
  12. 2023 Medium

    Mapped Fyn phosphorylation of TGM2 at Tyr369 regulating renal autophagy and extended the SDC1 trafficking complex to FLOT1 and BHMT for radioresistance.

    Evidence Phospho-proteomics/in vitro kinase assay for Y369, TMT proteomics and co-IP for SDC1-TGM2-FLOT1-BHMT complex, STZ and GBM models

    PMID:37190106 PMID:37441590

    Open questions at the time
    • Functional consequence of Y369 phosphorylation on enzymatic activity not defined
    • Partly overlapping single-lab GBM studies
  13. 2024 Medium

    Showed S-glutathionylation, driven by GSTP1 under oxidative stress, degrades TGM2 and disrupts its nuclear topoisomerase IIα interaction, controlling DNA double-strand break repair.

    Evidence Co-IP of TGM2–topoisomerase IIα, S-glutathionylation detection, γH2AX assays, GSTP1 manipulation, U87 xenografts

    PMID:39580966

    Open questions at the time
    • Whether TGM2 enzymatically modifies topoisomerase IIα unknown
    • Single lab
  14. 2025 High

    Established TGM2 as a chromatin-modifying enzyme recruited by TIF1β to MYC target loci to install H3Q5 serotonylation and activate oncogenic transcription.

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

    PMID:39788430

    Open questions at the time
    • How TIF1β selects specific MYC loci unresolved
    • Reader proteins for H3Q5ser not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TGM2's multiple activities (transamidase, GTP-binding, PDI) are coordinately switched within a single cell, and the rules governing its localization between surface, cytosol, mitochondria-associated membranes, and nucleus, remain unresolved.
  • No unified structural model linking PTM state to activity selection
  • Trafficking determinants between compartments incompletely defined
  • Physiological serotonylation substrate repertoire largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0003924 GTPase activity 2 GO:0042393 histone binding 2 GO:0098631 cell adhesion mediator activity 2 GO:0016853 isomerase activity 1
Localization
GO:0031012 extracellular matrix 4 GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-73894 DNA Repair 1 R-HSA-8953897 Cellular responses to stimuli 1
Partners
GPR56ITGB1ITGB3MAP1LC3BS100A4SDC1SDC4STAT1
Complex memberships
GPR56-Gαq-CD81 complexSDC1-TGM2-FLOT1-BHMT complexTGM2-integrin co-receptor complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 GPR56 binds specifically to tissue transglutaminase TG2 in the extracellular matrix, and this interaction suppresses melanoma tumor growth and metastasis; GPR56 associates in a complex with Gαq and the tetraspanin CD81. Co-immunoprecipitation, binding assays, overexpression/knockdown experiments, xenograft tumor models Proceedings of the National Academy of Sciences of the United States of America High 16757564
2013 GPR56 antagonizes TG2 function in melanoma by internalizing and degrading extracellular TG2, leading to decreased fibronectin deposition and impaired focal adhesion kinase accumulation; TG2 crosslinking activity promotes melanoma growth. Xenograft studies in immunodeficient Tg2-/- mice, cell-based internalization/degradation assays Cancer research High 24356421
2006 TG2 associates with β1 and β5 integrins on the surface of drug-resistant MCF-7 breast cancer cells, and this interaction strongly activates focal adhesion kinase, promoting fibronectin-mediated cell attachment and survival; siRNA knockdown of TG2 inhibits these functions. Co-immunoprecipitation, siRNA knockdown, fibronectin attachment assays, FAK activation assays Oncogene High 16449978
2009 Increased TG2 expression in fibroblasts activates NF-κB, resulting in upregulation of TGFβ1 expression and secretion of biologically active TGFβ1, leading to increased collagen and fibronectin synthesis and deposition; this process requires TG2 transamidase activity and can be inhibited by nitric oxide (via S-nitroso-N-acetylpenicillamine), which reduces TG2 activity and arrests the inactive enzyme on the cell surface. Tetracycline-inducible TG2 expression in Swiss 3T3 fibroblasts, site-directed TG inhibitor, NF-κB reporter assay, NO donor treatment The Journal of biological chemistry High 19657147
2011 TG2 transamidating activity is the primary biochemical function required for both apoptosis protection and autophagosome formation; TG2 knockout MEF cells show exacerbated caspase-3 and PARP cleavage upon apoptotic stimuli and accumulation of LC3-II upon autophagy induction, whereas reconstitution with wild-type TG2 but not the transamidation-inactive C277S mutant rescues both phenotypes. TG2 knockout MEF reconstitution with WT or C277S mutant TG2, caspase-3 activity assays, PARP cleavage, LC3-II immunoblotting Amino acids High 21479826
2005 TG2 acting as a G protein mediates intracellular signaling via the α1b-adrenergic receptor in hepatocytes, and this signaling regulates Bcl-xL expression; TG2-/- mice show increased hepatocyte sensitivity to Fas-mediated apoptosis with decreased Bcl-xL levels, while Fas receptor levels, FLIP(L), and IκBα degradation are unchanged. TG2 knockout mice, anti-Fas antibody challenge (in vivo and in vitro), Bcl-xL/FLIP(L) immunoblotting, cell-surface Fas quantification Hepatology (Baltimore, Md.) High 16108039
2013 TG2 directly interacts with S100A4 and crosslinks it (polymerizes it); S100A4 is a TG2 substrate. Inhibition of TG2 (by inhibitors or shRNA) blocks S100A4-accelerated mammary tumor cell migration. The signaling mechanism involves syndecan-4 and α5β1 integrin co-signaling linked by PKCα activation. Co-immunoprecipitation, Far Western blotting, crosslinking assays, TG2 inhibitors (cell-permeable and non-cell-permeable), shRNA knockdown, functional blocking antibodies PloS one High 23469180
2012 PKA-induced phosphorylation of TG2 at serine-216 is required for TG2-mediated activation of NF-κB, Akt phosphorylation, and downregulation of PTEN; a mutant TG2 lacking Ser216 (m-TG2) fails to activate NF-κB and Akt, and fails to suppress PTEN, indicating this PTM controls TG2's pro-survival signaling. TG2-null MEF reconstitution with WT or Ser216A mutant TG2, NF-κB reporter assay, immunoblotting, FACS, cell migration assay; confirmed in MCF-7 and T-47D breast cancer cells BMC cancer Medium 22759359
2018 TG2, dependent on its protein disulfide isomerase (PDI) activity, triggers trimerization and nuclear translocation of HSF1, activating the heat-shock response; loss of TG2 correlates with defective HSF1 nuclear translocation and reduced binding to the HSP70 promoter. TG2 absence impairs the HSF1-HSP70 pathway in cystic fibrosis cells and increases CFTR function by ~40% in TG2-/- CF mouse models. TG2 knockout mice (CF model), TG2 loss-of-function in cells, HSF1 DNA-binding/promoter assay, nuclear translocation imaging, CFTR functional measurement EMBO reports High 29752334
2022 TGM2-mediated histone serotonylation (monoaminylation of H3Q5) is excluded from constitutive heterochromatic regions because higher-order chromatin structure imposes a steric barrier; nucleosome-level studies show steric hindrance restricts TGM2 activity to accessible histone tail sites, with substrate accessibility—not primary sequence or pre-existing PTMs—being the primary determinant of TGM2-mediated histone monoaminylation. Biochemical histone serotonylation assays with chromatin substrates, DNA-barcoded nucleosome libraries, structure-activity relationship studies, mammalian cell chromatin mapping 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) and facilitates IP3R1–VDAC1 interactions, resulting in mitochondrial calcium influx and mtROS accumulation; TGM2 silencing inhibits IP3R1–VDAC1 tethering and prevents high glucose-induced mitochondrial calcium overload. TGM2 siRNA knockdown, co-immunoprecipitation of IP3R1-VDAC1, mitochondrial calcium measurement (Fluo-4AM), mtROS assay, STZ-induced diabetic mouse model Cell death and differentiation Medium 32704090
2022 After irradiation, TGM2 binds SDC1 and is transported from the cell membrane to lysosomes; TGM2 then binds LC3 through two LC3-interacting regions (LIRs), coordinating autophagosome-lysosome fusion by enabling lysosomal EPG5 to recognize LC3 and stabilize the STX17-SNAP29-VAMP8 SNARE complex assembly, thereby promoting radioresistance in glioblastoma. Co-immunoprecipitation, confocal imaging of autophagosome-lysosome fusion, mRFP-GFP-LC3 reporter, LIR mutation analysis, TGM2 inhibitor (cystamine) in orthotopic GBM mice Autophagy High 35913916
2023 After irradiation, SDC1 carries TGM2 from the cell membrane into cytoplasm and transports it to lysosomes via flotillin 1 (FLOT1); TGM2 then recognizes BHMT on autophagosomes to coordinate autophagosome-lysosome encounter, forming the SDC1-TGM2-FLOT1-BHMT complex that maintains autophagic flux and enhances GBM radioresistance. Co-immunoprecipitation, TMT quantitative proteomics, immunofluorescence, mRFP-GFP-LC3, transmission electron microscopy, colony formation assays Theranostics Medium 37441590
2022 Cytosolic TGM2 suppresses TRIM21-mediated ubiquitination and degradation of STAT1 by facilitating dissociation of the TRIM21–STAT1 complex; this requires TGM2's GTP-binding enzymatic activity (not transamidase activity), stabilizing STAT1 and promoting gastric cancer progression. TRIM21 is identified as the E3 ubiquitin ligase for STAT1 in gastric cancer. Co-immunoprecipitation, mass spectrometry, TGM2 GTP-binding mutants, calcium ionophore (A23187) to abolish GTP-binding activity, ubiquitination assays, xenograft models Cancer communications (London, England) High 36353796
2016 TG2 forms complexes with NF-κB components and induces IL-6 production, which in turn triggers enhanced autophagy in drug-resistant mantle cell lymphoma cells through STAT3 signaling; ATG5 positively feeds back to regulate TG2/NF-κB/IL-6 signaling, constituting a positive feedback loop for MCL cell survival. CRISPR-mediated TG2 silencing, TG2 overexpression, co-immunoprecipitation with NF-κB components, autophagy assays, IL-6 measurements, xenograft models Cancer research Medium 27488529
2010 Active TG2 directly interacts with β3 integrins (demonstrated by co-immunoprecipitation), acting as a co-receptor for fibronectin; active TG2 (but not the C277S transamidation-inactive mutant) increases TGFβ1 levels and matrix-deposited fibronectin in CT26 colon carcinoma cells, increasing cell adhesion and reducing migration/invasion. Stable transfection of WT vs. C277S TG2 mutant in CT26 cells, immunoprecipitation of TG2-β3 integrin complex, TG2 site-directed inhibitors, TGFβ1 ELISA, fibronectin deposition assays Amino acids Medium 21046178
2015 Inhibition of TG2 transamidase activity with a cell-permeable fluorescent peptidomimetic inhibitor blocks TG2 binding to cell surface syndecan-4, inhibits translocation of TG2 into the ECM, and reduces fibronectin deposition, cell motility, and cord formation; in a mouse model of hypertensive nephrosclerosis, TG2 inhibition reduced collagen deposition by >40%. Fluorescently labeled cell-permeable TG2 inhibitor, live-cell imaging, fibronectin deposition assays, Matrigel cord assay, hypertensive nephrosclerosis mouse model Chemistry & biology Medium 26456735
2007 Missense mutations in TGM2 located near the catalytic site (N333S, M330R, I331N) impair transamidating activity in vitro; TG2 is the only transglutaminase significantly expressed in human pancreatic islet cells, and Tgm2-/- mice are glucose-intolerant with impaired insulin secretion. In vitro transamidation activity assay of mutant TG2 proteins, gene expression analysis in human pancreas, Tgm2 knockout mouse phenotyping (glucose tolerance test) Human mutation Medium 17939176
2020 Hypoxia enhances TG2 expression and activity in pulmonary vein smooth muscle cells (hPVSMC) in a HIF-2-dependent manner; TG2 mediates serotonylation (covalent serotonin modification) of SERCA2, inhibiting SERCA2 activity and increasing cytosolic calcium via TRPC6-mediated calcium influx; vascular smooth muscle-specific Tgm2-/- mice are protected from hypoxia-induced pulmonary hypertension. Co-immunoprecipitation of TG2 and SERCA2, TG2 gene silencing/overexpression, calcium imaging (Fluo-4AM), smooth muscle-specific TG2 knockout mice, hypoxic pulmonary hypertension model (RVSP, RVHI measurements) Frontiers in pharmacology High 32116663
2022 Lung-resident neutrophils express TGM2, which is induced by PGE2 via protein kinase A (PKA) signaling; TGM2 mediates the immune-suppressive phenotype of lung neutrophils, and Tgm2-/- mice release high levels of inflammatory cytokines and show exacerbated lung damage in LPS-induced acute respiratory distress syndrome. Tgm2-/- mice, LPS-induced ARDS model, bronchoalveolar lavage fluid treatment of bone marrow neutrophils, PGE2/PKA pathway pharmacological dissection Blood Medium 35679477
2010 TG2 overexpression in neuroblastoma SH-SY5Y cells protects against etoposide-induced cell death; this protection requires transamidase activity since the C277S inactive mutant fails to suppress caspase-3 activation and p53 phosphorylation. Overexpression of WT vs. C277S TG2 mutant, antisense TG2 knockdown, caspase-3 activity assay, p53 phosphorylation immunoblotting Amino acids Medium 20112034
2016 PARP3 promotes TGFβ-induced EMT by stimulating a TG2-Snail-E-cadherin axis; PARP3 depletion prevents TGFβ-dependent induction of TG2 and Snail expression, dissolution of cell junctions, and acquisition of cell motility. PARP3 siRNA depletion, TGFβ stimulation, immunoblotting for TG2/Snail/E-cadherin, cell motility assays, mammary epithelial and breast cancer cell models Oncotarget Medium 27579892
2022 Weakly migratory metastatic breast cancer cells release microvesicles rich in TG2, which activate murine fibroblasts and lead weakly migratory cancer cell migration in vitro; these microvesicles induce tumor stiffening and fibroblast activation in vivo and enhance metastasis of weakly migratory cells. Microvesicle isolation, TG2 content analysis, fibroblast activation assays, in vitro migration, in vivo tumor stiffness and metastasis models eLife Medium 36475545
2023 Fyn tyrosine kinase phosphorylates TGM2 on tyrosine-369 (Y369); Fyn-dependent phosphorylation of TGM2 regulates autophagy in proximal renal tubules, and TGM2 knockdown decreases p53 expression in autophagic conditions, identifying a Fyn-TGM2-p53 axis in diabetic kidney disease. Phospho-proteomic analysis, in vitro kinase assay, TGM2 knockdown in proximal tubule cells, STZ-induced hyperglycemic mouse model, immunoblotting Cells Medium 37190106
2025 TGM2 catalyzes H3Q5 serotonylation (H3Q5ser) in hepatocellular carcinoma; transcriptional intermediary factor 1β (TIF1β) mediates recruitment of TGM2 to MYC target gene loci, facilitating H3Q5ser modifications that promote MYC pathway gene expression and HCC progression. CUT&Tag (chromatin profiling), RNA sequencing, adeno-associated virus liver-specific TGM2/H3.3 overexpression, HCC organoids, xenograft and hydrodynamic tail vein injection models, TGM2 inhibitor treatment Journal of hepatology High 39788430
2016 In microglia, TGM2's proinflammatory effects are dependent on its GTP-binding activity rather than transamidase activity; TGM2 activates the NF-κB signaling pathway to facilitate microglial activation, and propofol inhibits microglial inflammation by suppressing TGM2 expression and downstream NF-κB signaling. TGM2 siRNA knockdown, gain-of-function overexpression with GTP-binding vs. transamidase activity mutants, NF-κB signaling assays, BV2 cells and primary microglia Journal of immunology research Medium 34485533
2024 RSL3-induced oxidative stress promotes S-glutathionylation of TGM2 via upregulation of GSTP1, leading to proteasomal degradation of TGM2; this suppresses nuclear accumulation of TGM2 and disrupts TGM2–topoisomerase IIα interaction after irradiation, impairing DNA DSB repair and sensitizing glioma cells to radiation. TGM2 overexpression/knockdown, co-immunoprecipitation of TGM2-topoisomerase IIα, S-glutathionylation detection, γH2AX DSB assay, GSTP1 manipulation, U87 xenograft model Redox biology Medium 39580966
2013 TG2 inhibition (by site-directed irreversible inhibitors or antisense transfection) blocks tubular structure formation in a vasculogenic mimicry model; TG2 in situ activity co-localizes with fibronectin and collagen IV in tube structures, and non-cell-permeable TG inhibitors reduce ECM deposition, indicating TG2's contribution to tube formation is extracellular. TG2 antisense transfection, cell-permeable and non-cell-permeable TG2 site-directed inhibitors, in situ TG activity assay, co-localization with fibronectin/collagen IV, tube formation assay Amino acids Medium 22231926
2017 TG2 and FXIII-A control monocyte-macrophage differentiation into osteoclasts and regulate RANKL production in mesenchymal stem cells and adipocytes; TG2/FXIII-A-deficient mice show increased osteoclastogenesis and trabecular bone loss, while TG2/FXIII-A-null MSCs show defective plasma fibronectin assembly. TG2 and FXIII-A double-knockout mice, in vitro osteoclastogenesis assays, chemical TG activity inhibition, bone histomorphometry, FN assembly assays Cell death and differentiation Medium 28387755
2020 AFF1 binds directly to the promoter region of the Tgm2 gene and regulates its transcription; AFF1 depletion enhances adipogenic differentiation of hMSCs, and overexpression of TGM2 largely rescues adipogenic differentiation in AFF1-deficient cells, placing TGM2 downstream of AFF1 in adipogenesis. ChIP-qPCR demonstrating AFF1 binding to TGM2 promoter, AFF1 siRNA and overexpression, TGM2 overexpression rescue, oil red O staining, in vivo adipose formation assay Cell proliferation Medium 32441391
2016 TG2 activity is increased in mast cells activated via IgE; serum TG2 activity is elevated in CSU patients and positively correlates with inflammatory mediator levels (histamine, LTC4, TNF-α, TGF-β, IL-4, IL-5, IL-6), and TG2 co-localizes with the mast cell marker c-kit in CSU lesional skin. Serum TG2 ELISA activity assay, IgE-activated CBMC and PBMC-derived mast cells, immunofluorescence co-localization in skin biopsies Annals of allergy, asthma & immunology Low 27613463

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 227 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 142 32704090
2021 Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling. BMC cancer 129 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 103 16146777
2011 TG2, a novel extracellular protein with multiple functions. Amino acids 98 21818567
2019 MiR-532-3p suppresses colorectal cancer progression by disrupting the ETS1/TGM2 axis-mediated Wnt/β-catenin signaling. Cell death & disease 97 31570702
2020 Tunable bioactivity and mechanics of collagen-based tissue engineering constructs: A comparison of EDC-NHS, genipin and TG2 crosslinkers. Biomaterials 94 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 88 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 85 29355739
2008 The transglutaminase 2 gene (TGM2), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer. Carcinogenesis 82 18174247
2016 PARP3 controls TGFβ and ROS driven epithelial-to-mesenchymal transition and stemness by stimulating a TG2-Snail-E-cadherin axis. Oncotarget 71 27579892
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 70 25215932
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
2010 A profiling platform for the characterization of transglutaminase 2 (TG2) inhibitors. Journal of biomolecular screening 67 20395409
2013 GPR56 inhibits melanoma growth by internalizing and degrading its ligand TG2. Cancer research 60 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) 59 36353796
2013 TGM2 and implications for human disease: role of alternative splicing. Frontiers in bioscience (Landmark edition) 59 23276939
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 55 35913916
2016 TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy. Cancer research 51 27488529
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 49 36639156
2017 Tampering with cancer chemoresistance by targeting the TGM2-IL6-autophagy regulatory network. Autophagy 48 28056186
2019 TGM2 interference regulates the angiogenesis and apoptosis of colorectal cancer via Wnt/β-catenin pathway. Cell cycle (Georgetown, Tex.) 46 31010374
2015 Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions. Chemistry & biology 46 26456735
2016 Role of tissue transglutaminase-2 (TG2)-mediated aminylation in biological processes. Amino acids 45 27270573
2011 TG2 transamidating activity acts as a reostat controlling the interplay between apoptosis and autophagy. Amino acids 44 21479826
2007 GPR56 and TG2: possible roles in suppression of tumor growth by the microenvironment. Cell cycle (Georgetown, Tex.) 44 17314516
2005 Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice. Hepatology (Baltimore, Md.) 43 16108039
2013 The role of TG2 in regulating S100A4-mediated mammary tumour cell migration. PloS one 42 23469180
2013 Up-regulation of TGM2 with ITGB1 and SDC4 is important in the development and metastasis of renal cell carcinoma. Urologic oncology 42 23499501
2015 Silencing of TGM2 reverses epithelial to mesenchymal transition and modulates the chemosensitivity of breast cancer to docetaxel. Experimental and therapeutic medicine 41 26622499
2018 TG2 regulates the heat-shock response by the post-translational modification of HSF1. EMBO reports 40 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
2022 Unique characteristics of lung-resident neutrophils are maintained by PGE2/PKA/Tgm2-mediated signaling. Blood 36 35679477
2022 TGM2-mediated histone transglutamination is dictated by steric accessibility. Proceedings of the National Academy of Sciences of the United States of America 35 36256821
2021 The NEAT1_2/miR-491 Axis Modulates Papillary Thyroid Cancer Invasion and Metastasis Through TGM2/NFκb/FN1 Signaling. Frontiers in oncology 35 33738254
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 35 34902811
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
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 31 30015899
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 29 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) 28 37246171
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
2020 Role of TG2-Mediated SERCA2 Serotonylation on Hypoxic Pulmonary Vein Remodeling. Frontiers in pharmacology 26 32116663
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
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 25 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 25 24828664
2023 TG2 promotes amyloid beta aggregates: Impact on ER-mitochondria crosstalk, calcium homeostasis and synaptic function in Alzheimer's disease. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 36989728
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
2025 TGM2-mediated histone serotonylation promotes HCC progression via MYC signalling pathway. Journal of hepatology 21 39788430
2021 Propofol Suppresses Microglia Inflammation by Targeting TGM2/NF-κB Signaling. Journal of immunology research 21 34485533
2010 The role of tissue transglutaminase (TG2) in regulating the tumour progression of the mouse colon carcinoma CT26. Amino acids 21 21046178
2020 Blocking TG2 attenuates bleomycin-induced pulmonary fibrosis in mice through inhibiting EMT. Respiratory physiology & neurobiology 20 32006666
2017 Tissue transglutaminase (TG2) and mitochondrial function and dysfunction. Frontiers in bioscience (Landmark edition) 20 28199195
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
2008 Homocysteine-induced toxicity increases TG2 expression in Neuro2a cells. Amino acids 18 18594946
2023 TGM2, HMGA2, FXYD3, and LGALS4 genes as biomarkers in acquired oxaliplatin resistance of human colorectal cancer: A systems biology approach. PloS one 17 37535601
2022 Implications of enigmatic transglutaminase 2 (TG2) in cardiac diseases and therapeutic developments. Biochemical pharmacology 17 35617996
2017 Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia. Cell death & disease 17 28151477
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
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
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
2024 RSL3 sensitizes glioma cells to ionizing radiation by suppressing TGM2-dependent DNA damage repair and epithelial-mesenchymal transition. Redox biology 14 39580966
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
2022 Role of TGM2 in T‑cell lymphoblastic lymphoma via regulation of IL‑6/JAK/STAT3 signalling. Molecular medicine reports 14 35014680
2021 TG2-gluten complexes as antigens for gluten-specific and transglutaminase-2 specific B cells in celiac disease. PloS one 14 34731200
2021 ETS1 Ameliorates Hyperoxia-Induced Alveolar Epithelial Cell Injury by Regulating the TGM2-Mediated Wnt/β-Catenin Pathway. Lung 14 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 Tubuloside A alleviates postmyocardial infarction cardiac fibrosis by inhibiting TGM2: Involvement of inflammation and mitochondrial pathway apoptosis. International immunopharmacology 11 39393274
2024 Tumor-associated macrophages induce epithelial-mesenchymal transition and promote lung metastasis in breast cancer by activating the IL-6/STAT3/TGM2 axis. International immunopharmacology 11 39426226
2023 TGM2 accelerates migration and differentiation of BMSCs by activating Wnt/β-catenin signaling. Journal of orthopaedic surgery and research 11 36872331
2023 Fyn Phosphorylates Transglutaminase 2 (Tgm2) and Modulates Autophagy and p53 Expression in the Development of Diabetic Kidney Disease. Cells 11 37190106
2022 Multi-Omics Analysis of Glioblastoma and Glioblastoma Cell Line: Molecular Insights Into the Functional Role of GPR56 and TG2 in Mesenchymal Transition. Frontiers in oncology 11 35600402
2019 Assessment of expression and specific activities of transglutaminases TG1, TG2, and FXIII-A during osteoclastogenesis. Analytical biochemistry 11 31786225
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
2021 The Multifaceted Role of HSF1 in Pathophysiology: Focus on Its Interplay with TG2. International journal of molecular sciences 10 34198675
2016 P2X7 receptor-mediated TG2 externalization: a link to inflammatory arthritis? Amino acids 10 27562793

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