TGM2

Transglutaminase 2 (TGM2, TG2) is the most ubiquitously expressed member of the transglutaminase family and functions as a multifunctional enzyme that catalyzes protein transamidation while also exhibiting GTP-binding and GTP-hydrolyzing activities involved in signal transduction^[1][2]. Mechanistically, TGM2-mediated protein crosslinking, post-translational modification, and conformational switching between GTP-bound closed and calcium-bound open states regulate cellular differentiation, cell adhesion, endocytosis, and cell death pathways^[2][3]. Through these activities, TGM2 contributes to diverse physiological processes in neural and non-neural tissues and participates in extracellular matrix remodeling through both enzymatic and non-enzymatic interactions^[1][2]. Dysregulated TGM2 expression or activity has been implicated in neurodegenerative disorders, celiac disease, fibrosis, and multiple cancers, where it influences tumor survival, progression, inflammation, angiogenesis, metastasis, and therapeutic resistance^[1][3][4][5]. In experimental tumor models, elevated TGM2 expression is associated with aggressive phenotypes, whereas stabilization of the open conformational state can induce cytotoxic effects in cancer cells^[3][5]. Compared with other transglutaminase family members that display tissue-restricted expression patterns, TGM2 is distinguished by its ubiquitous distribution, multifunctional catalytic repertoire, and dual transamidase/GTP-binding activities^[1]. Alternative TGM2 isoforms exhibit distinct biological functions; notably, the TG2-S isoform lacks a critical C-terminal residue required for GTP-dependent regulation, promoting constitutive transamidase activity and cellular differentiation, whereas TG2-L represses differentiation and supports cell growth in neuroblastoma models^[1]. For experimental applications, small-molecule inhibitors including TTGM5826 and LM11 have been used to stabilize cytotoxic open conformations of TGM2 and suppress cancer cell growth, supporting TGM2 as a mechanistically informative therapeutic target^[1][3].