Transglutaminase Interaction with α6/β4-Integrin Stimulates YAP1-Dependent ΔNp63α Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation.
Transglutaminase Interaction with α6/β4-Integrin Stimulates YAP1-Dependent ΔNp63α Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation.
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DOI：
10.1158/0008-5472.can-16-2032
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发表时间：
2016-12-15
期刊：
影响因子：
11.2
通讯作者：
Eckert RL
中科院分区：
文献类型：
--
作者：
Fisher ML;Kerr C;Adhikary G;Grun D;Xu W;Keillor JW;Eckert RL
转谷氨酰胺酶 2 (TG2) 的表达是表皮鳞状细胞癌干细胞存活所必需的。然而，TG2 触发的介导这种生存行为的分子信号传导机制尚不清楚。在这里，我们发现 TG2 在 ECS 细胞中组成型表达，与 α6/β4 整合素相互作用，刺激 FAK 和 Src 信号传导，导致磷酸肌醇依赖性激酶 1 (PDK1) 的磷酸肌醇 3 激酶 (PI3K) 激活。 PDK1 抑制 Hippo 信号传导，导致 YAP1 的核积累增强，YAP1 与 ΔNp63α 相互作用并稳定 ΔNp63α，从而增强 ECS 细胞球体形成、侵袭和迁移。总体而言，这些发现表明，组成型 TG2 表达导致 ΔNp63α 稳定，从而维持癌症干细胞特性并增强肿瘤形成。
Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem cell survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show that TG2 is constitutively expressed in ECS cells where it interacts with α6/β4 integrin to stimulate FAK and Src signaling, leading to phosphoinositide 3 kinase (PI3K) activation of phosphoinositide dependent kinase 1 (PDK1). PDK1 inhibits Hippo signaling, leading to enhanced nuclear accumulation of YAP1, which interacted with and stabilized ΔNp63α to enhance ECS cell spheroid formation, invasion, and migration. Overall, these findings suggest that constitutive TG2 expression results in stabilization of ΔNp63α, leading to maintenance of cancer stem cell properties and enhanced tumor formation.