Protein-glutamine gamma-glutamyltransferase 2 (TGM2) belongs to the transglutaminase family, which is ubiquitously expressed in various cell types and involved in many key cellular processes, including cell growth, proliferation, differentiation, migration, and apoptosis. TGM2 is a multifunctional protein whose activities can be divided into calcium-dependent (such as transaminases and deaminases) and calcium-independent (such as GTPases, ATPases, protein kinases, and dithiothreose isomerases). TGM2 plays an important role in tumorigenesis and progression.
(Data source: Li H, et al. Biosci Rep. 2024)
Expression distribution of TGM2
TGM2 is mainly expressed in endometrial stromal cells, syncytiotrophoblasts, cytotrophoblasts, ductal cells, endothelial cells, cardiomyocytes, and smooth muscle cells.
(Data source: unprot)
The structure of TGM2 and its receptor
TGM2 is a secreted protein composed of 687 amino acids, whose structure includes an N-terminal β-sandwich domain, a catalytic core (containing the Cys277-His335-Asp358 triad) and two C-terminal β-barrel domains.
N-terminal β-sandwich domain: This domain can bind to extracellular matrix proteins (such as fibronectin), helping TGM2 to localize to the cell membrane and extracellular matrix.
Catalytic core: The catalytic triad (Cys277, His335, Asp358) within the core is responsible for carrying out the acyl transfer reaction. Its activity is tightly regulated by calcium ions (Ca²⁺) and guanosine triphosphate (GTP), making TGM2 act like a " molecular switch. " In the intracellular environment of low calcium and high GTP, TGM2 is in a closed, inactive state, primarily involved in GTP-mediated signal transduction. When calcium concentrations rise, the enzyme changes conformation, exposing the catalytic site and enabling transamidation or deamidation.
C-terminal β-barrel domain: These two domains are involved in the conformational flexibility and regulation of the enzyme.
(Data source: Alphafold)
The role of TGM2 in cancer
Overexpression of TGM2 can promote cancer cell growth through multiple cell proliferation pathways and inhibit apoptosis. TGM2 directly binds to and inhibits the tumor suppressor p53, thereby impeding caspase-3-mediated apoptosis and inducing tumor escape in colorectal cancer. TGM2 also inhibits the JNK/BCL-2 pathway, thereby alleviating apoptosis. TGM2 interacts with multiple factors in the KRAS pathway and is associated with KRAS mutation-induced cancer development. Furthermore, TGM2 can upregulate the Wnt/β-catenin pathway to inhibit apoptosis and promote tumorigenesis. Typically, overexpression of TGM2 is associated with the upregulation of several stemness markers, including CD133 , SOX2, and β-catenin, thereby driving the self-renewal pathways of cancer stem cells.
(Data source: Li H, et al. Biosci Rep. 2024)
TGM2 -targeted therapy
Zampilimab, a monoclonal antibody targeting TGM2, is being developed by UCB for the treatment of fibrotic diseases such as idiopathic pulmonary fibrosis (IDF) and chronic kidney disease (CAI). NCT04335578 is a multicenter, randomized, placebo-controlled, investigator-blinded, and participant-blinded study evaluating the safety and tolerability, pharmacokinetics, and pharmacodynamics of zampilimab in adult renal transplant recipients with chronic allograft damage. This study is currently terminated, and no new research updates have been found.
(Data source: UCB official website)
