TGM2 (Transglutaminase 2) - Structure, Function, and Clinical Significance
A multifunctional enzyme involved in crosslinking, signaling, and disease pathogenesis
Gene Information Card
| Symbol | TGM2 |
|---|---|
| Full Name | Transglutaminase 2 |
| Gene Type | Protein coding |
| Chromosomal Location | 20q11.23 |
| NCBI Gene ID | 7052 ncbi.nlm.nih.gov/gene/7052 |
| Ensembl ID | ENSG00000198959 |
| UniProt ID | P21980 |
| OMIM ID | 190196 |
| HGNC ID | 11778 |
| Aliases | TG2, tTG, transglutaminase C, G-α-h, GNAH |
Description
The TGM2 gene encodes transglutaminase 2 (TG2), a calcium-dependent enzyme that catalyzes protein crosslinking via transamidation, as well as deamidation and polyamination. TG2 also exhibits GTPase activity and functions as a G protein in intracellular signaling. It is ubiquitously expressed and localizes to multiple cellular compartments including cytosol, nucleus, mitochondria, and extracellular matrix. TG2 is involved in diverse physiological processes such as apoptosis, cell adhesion, wound healing, and extracellular matrix stabilization. Dysregulation of TG2 is linked to several diseases, including celiac disease, cancer, fibrosis, and neurodegenerative disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Celiac Disease | TG2 deamidates gluten peptides, increasing their immunogenicity and triggering an autoimmune response in genetically susceptible individuals. | Strong evidence: TG2 is the autoantigen in celiac disease; anti-TG2 antibodies are diagnostic markers. |
| Cancer (various types) | TG2 promotes tumor progression, metastasis, and chemoresistance through activation of NF-κB, PI3K/Akt, and integrin signaling; also contributes to epithelial-mesenchymal transition (EMT). | Evidence from multiple studies: overexpression in pancreatic, breast, ovarian, and lung cancers; knockdown reduces tumor growth in xenograft models. |
| Fibrosis (liver, kidney, lung) | TG2 crosslinks extracellular matrix proteins, increasing resistance to degradation and promoting fibrotic tissue accumulation. | Evidence: elevated TG2 activity in fibrotic tissues; TG2 inhibitors reduce fibrosis in animal models. |
| Neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's) | TG2 crosslinks and aggregates proteins such as amyloid-β, α-synuclein, and huntingtin, contributing to neuronal toxicity. | Evidence: increased TG2 expression and activity in affected brain regions; inhibition reduces protein aggregation in cell models. |
| Celiac disease (refractory) | In refractory celiac disease, TG2 may contribute to aberrant T-cell responses and enteropathy. | Evidence: persistent TG2 antibodies and TG2-specific T cells in refractory cases. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lung | 18.6 | Medium |
| Small intestine | 15.2 | Medium |
| Kidney | 12.4 | Medium |
| Liver | 10.1 | Low |
| Heart | 8.3 | Low |
| Brain | 5.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 25.3 | High expression; used in many TG2 studies |
| A549 (lung cancer) | 18.7 | Moderate; involved in EMT and drug resistance |
| HepG2 (liver cancer) | 12.1 | Moderate; associated with fibrosis |
| MCF7 (breast cancer) | 9.8 | Low; but induced under stress |
| SH-SY5Y (neuroblastoma) | 6.4 | Low; relevant to neurodegeneration studies |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.829G>A (p.Val277Ile) | Missense | Rare (MAF <0.01) | Alters GTPase activity; may affect signaling |
| c.1123C>T (p.Arg375Cys) | Missense | Rare | Reduced transamidation activity; associated with celiac disease risk |
| c.1550A>G (p.Asn517Ser) | Missense | Rare | Affects protein stability; unknown clinical significance |
| c.1963G>A (p.Val655Met) | Missense | Rare | Potential impact on substrate binding; not well characterized |
Mutation functional classification
Loss of Function (LOF)
Mutations that reduce transamidation or GTPase activity, such as p.Arg375Cys, may impair TG2's role in apoptosis and matrix remodeling, potentially contributing to disease susceptibility.
Gain of Function (GOF)
Overexpression or activating mutations (not well-defined) can enhance crosslinking and signaling, promoting fibrosis and cancer progression.
Dominant Negative (DN)
Some mutations may interfere with TG2 dimerization or substrate binding, exerting a dominant-negative effect on wild-type function, though specific examples are not well documented.
View complete mutation data：
Gene Ontology (GO)
| • protein-glutamine gamma-glutamyltransferase activity | • GTPase activity |
| • calcium ion binding | • protein binding |
| • identical protein binding | • kinase activity |
| • signal transducer activity | • extracellular matrix structural constituent |
| • apoptotic process | • cell adhesion |
| • signal transduction | • protein crosslinking |
| • response to stress | • wound healing |
Pathways
• Apoptosis
• NF-kappa B signaling
• PI3K-Akt signaling
• Integrin signaling
• Extracellular matrix organization
• G protein-coupled receptor signaling (via Gαh)
Protein Summary
Transglutaminase 2 (TG2) is a 78 kDa multifunctional protein with three main enzymatic activities: transamidation (calcium-dependent crosslinking), deamidation, and GTP hydrolysis. It also acts as a G protein (Gαh) in adrenergic receptor signaling. TG2 is predominantly intracellular but can be secreted to the extracellular matrix where it stabilizes matrix proteins. Its activity is tightly regulated by calcium and GTP. In disease, TG2's crosslinking activity contributes to fibrosis and protein aggregation, while its signaling roles promote cancer cell survival and metastasis. TG2 is a major autoantigen in celiac disease, where it deamidates gluten peptides, enhancing their immunogenicity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TGM2 Knockout HEK293 Cell Line | EDJ-KQ2581 | Human | 7052 | Details Get a Quote |
| TGM2 Knockout HeLa Cell Line | EDJ-KQ21900 | Human | 7052 | Details Get a Quote |
| TGM2 Knockout A-549 Cell Line | EDJ-KQ23266 | Human | 7052 | Details Get a Quote |
| TGM2 Knockout HCT 116 Cell Line | EDJ-KQ23267 | Human | 7052 | Details Get a Quote |
| TGM2 Knockout MDCK Cell Line | EDJ-KZ507 | Dog | 485867 | Details Get a Quote |
