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.

中文翻译：

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组织转谷氨酰胺酶2通过增加收缩力来调节肿瘤细胞的张力稳态。

现在，异常的张力性细胞稳态被认为是癌症的标志。尽管如此，这种异常的根源仍不清楚。在这项工作中，我们研究了组织转谷氨酰胺酶2（TG2，也称为TGM2）的作用，该蛋白与预后不良和转移潜力增加有关，以及其与EGF受体在调节肿瘤细胞机械状态中的关系。值得注意的是，在使用药理学和基于shRNA的方法的实验中，我们观察到了TG2介导的粘着斑成分的调制以及刚度诱导的FAK活化，这与细胞收缩力的显着提高有关。另外，在TG2表达后，可在非恶性细胞中再现增加的收缩力。此外，TG2介导的细胞收缩力增加主要是由于EGFR介导的细胞收缩抑制作用的丧失。这些发现建立了细胞内TG2作为细胞张力动态平衡的调节剂，并表明存在信号开关，其控制生长因子受体在确定细胞机械状态中的作用。