Tissue transglutaminase 2 regulates tumor cell tensional homeostasis by increasing contractility

Abnormal tensional cellular homeostasis is now considered a hallmark of cancer. Despite this, the origin of this abnormality remains unclear. In this work, we investigated the role of tissue transglutaminase 2 (TG2, also known as TGM2), a protein associated with poor prognosis and increased metastatic potential, and its relationship to the EGF receptor in the regulation of the mechanical state of tumor cells. Remarkably, we observed a TG2-mediated modulation of focal adhesion composition as well as stiffness-induced FAK activation, which was linked with a distinctive increase in cell contractility, in experiments using both pharmacological and shRNA-based approaches. Additionally, the increased contractility could be reproduced in non-malignant cells upon TG2 expression. Moreover, the increased cell contractility mediated by TG2 was largely due to the loss of EGFR-mediated inhibition of cell contractility. These findings establish intracellular TG2 as a regulator of cellular tensional homeostasis and suggest the existence of signaling switches that control the contribution of growth factor receptors in determining the mechanical state of a cell.