The Outside-In Journey of Tissue Transglutaminase in Cancer

Tissue transglutaminase (TG2) is a member of the transglutaminase family that catalyzes Ca²⁺-dependent protein crosslinks and hydrolyzes guanosine 5'-triphosphate (GTP). The conformation and functions of TG2 are regulated by Ca²⁺ and GTP levels; the TG2 enzymatically active open conformation is modulated by high Ca²⁺ concentrations, while high intracellular GTP promotes the closed conformation, with inhibition of the TG-ase activity. TG2's unique characteristics and its ubiquitous distribution in the intracellular compartment, coupled with its secretion in the extracellular matrix, contribute to modulate the functions of the protein. Its aberrant expression has been observed in several cancer types where it was linked to metastatic progression, resistance to chemotherapy, stemness, and worse clinical outcomes. The N-terminal domain of TG2 binds to the 42 kDa gelatin-binding domain of fibronectin with high affinity, facilitating the formation of a complex with β-integrins, essential for cellular adhesion to the matrix. This mechanism allows TG2 to interact with key matrix proteins and to regulate epithelial to mesenchymal transition and stemness. Here, we highlight the current knowledge on TG2 involvement in cancer, focusing on its roles translating extracellular cues into activation of oncogenic programs. Improved understanding of these mechanisms could lead to new therapeutic strategies targeting this multi-functional protein.