A prominent feature of tumour cells is increased cell contractility, which is associated with greater metastatic potential. How tensional homeostasis is regulated, and what cellular mechanisms go awry in cancer is, however, not entirely clear. Here, Cynthia Reinhart-King, Francois Bordeleau and colleagues (Bordeleau et al., 2020) interrogate the role of the transglutaminase 2 (TG2) protein in controlling mechanotransduction and the mechanical state of the cell. Through clever pharmacological inhibition strategies complemented with shRNA-knockdown approaches, they first establish that intracellular TG2 influences focal adhesion number and organization. Further experiments that assess stiffness-mediated FAK activation and focal adhesion dynamics suggest a role for TG2 in modulating focal adhesion maturation and signalling. The authors then provide direct evidence that intracellular TG2 modulates cell contractility by performing traction force microscopy. Finally, they propose that TG2 influences contractility indirectly through the loss of epidermal growth factor receptor-mediated inhibition of contractility. This work advances our understanding of how tensional homeostasis is disrupted in tumours and provides new insights into the complex regulation of cell contractility by receptor tyrosine kinase receptors.
