Transglutaminase 2 (TG2) is an important mesothelioma cancer cell survival protein. However, the mechanism whereby TG2 maintains mesothelioma cell survival is not well understood. We present studies showing that TG2 drives hepatocyte growth factor (HGF)-dependent MET receptor signaling to maintain the aggressive mesothelioma cancer phenotype. TG2 increases HGF and MET messenger RNA and protein levels to enhance MET signaling. TG2 inactivation reduces MET tyrosine kinase activity to reduce cancer cell spheroid formation, invasion and migration. We also confirm that HGF/MET signaling is a biologically important mediator of TG2 action. Reducing MET level using genetic methods or treatment with MET inhibitors reduces spheroid formation, invasion and migration and this is associated with reduced MEK1/2 and ERK1/2. In addition, MEK1/2 and ERK1/2 inhibitors suppress the cancer phenotype. Moreover, MET knockout mesothelioma cells form 10-fold smaller tumors compared to wild-type cells and these tumors display reduced MET, MEK1/2, and ERK1/2 activity. These findings suggest that TG2 maintains HGF and MET levels in cultured mesothelioma cells and tumors to drive HGF/MET, MEK1/2, and ERK1/2 signaling to maintain the aggressive mesothelioma cancer phenotype.

中文翻译：

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转谷氨酰胺酶 2 增强肝细胞生长因子信号以驱动间皮瘤癌细胞表型

转谷氨酰胺酶 2 (TG2) 是一种重要的间皮瘤癌细胞存活蛋白。然而，TG2 维持间皮瘤细胞存活的机制尚不清楚。我们提出的研究表明，TG2 驱动肝细胞生长因子 (HGF) 依赖性 MET 受体信号传导以维持侵袭性间皮瘤癌症表型。TG2 增加 HGF 和 MET 信使 RNA 和蛋白质水平以增强 MET 信号。TG2 失活会降低 MET 酪氨酸激酶活性，从而减少癌细胞球体的形成、侵袭和迁移。我们还确认 HGF/MET 信号是 TG2 作用的生物学重要介质。使用遗传方法或使用 MET 抑制剂治疗降低 MET 水平可减少球体形成、侵袭和迁移，这与 MEK1/2 和 ERK1/2 减少有关。此外，MEK1/2 和 ERK1/2 抑制剂抑制癌症表型。此外，与野生型细胞相比，MET 敲除间皮瘤细胞形成的肿瘤小 10 倍，并且这些肿瘤表现出降低的 MET、MEK1/2 和 ERK1/2 活性。这些发现表明，TG2 维持培养的间皮瘤细胞和肿瘤中的 HGF 和 MET 水平，以驱动 HGF/MET、MEK1/2 和 ERK1/2 信号，从而维持侵袭性间皮瘤癌症表型。