Tissue Transglutaminase Is an Essential Participant in the Epidermal Growth Factor-stimulated Signaling Pathway Leading to Cancer Cell Migration and Invasion
Tissue Transglutaminase Is an Essential Participant in the Epidermal Growth Factor-stimulated Signaling Pathway Leading to Cancer Cell Migration and Invasion
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DOI：
10.1074/jbc.m109.013037
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发表时间：
2009-07-03
影响因子：
4.8
通讯作者：
Cerione, Richard A.
中科院分区：
文献类型：
--
作者：
Antonyak, Marc A.;Li, Bo;Cerione, Richard A.
表皮生长因子（EGF）在肿瘤发生过程中发挥多效作用，包括刺激细胞迁移和侵袭。虽然许多传统的信号蛋白（e。G. Ras和Rho GTP酶）与EGF刺激的癌细胞迁移有关，但对在该生长因子途径下游发挥作用的那些蛋白的身份知之甚少。在这里，我们使用HeLa癌细胞作为模型系统，用于研究组织转氨酶（TGase），一种与肿瘤发生有关的蛋白质，在EGF刺激的癌细胞迁移和侵袭中的作用。用EGF处理HeLa细胞导致TGase活化及其在其前沿的积累，而敲低TGase表达，或用TGase抑制剂处理细胞，阻断EGF刺激的细胞迁移和侵袭。我们发现，EGF信号通过Ras和c-Jun N-末端激酶负责将TGase靶向细胞的前缘并激活它。EGF正确定位和激活TGase的要求可以通过致癌Ras（G12 V）的表达来规避，其刺激迁移的能力也依赖于TGase。我们进一步表明，在高度侵袭性的乳腺癌细胞系MDAMB 231中，EGF刺激对于迁移和侵袭活性是不必要的，TGase已经处于前沿并被激活。这些发现表明，TGase在癌细胞运动性和侵袭性中起着关键作用，并且代表了以前未被重视的EGF途径参与者，该途径刺激癌细胞中的这些过程。
Epidermal growth factor (EGF) exerts pleiotropic effects during oncogenesis, including the stimulation of cell migration and invasiveness. Although a number of traditional signaling proteins (e. g. Ras and Rho GTPases) have been implicated in EGF-stimulated cancer cell migration, less is known about the identity of those proteins functioning further downstream in this growth factor pathway. Here we have used HeLa carcinoma cells as a model system for investigating the role of tissue transglutaminase (TGase), a protein that has been linked to oncogenesis, in EGF-stimulated cancer cell migration and invasion. Treatment of HeLa cells with EGF resulted in TGase activation and its accumulation at their leading edges, whereas knocking down TGase expression, or treating cells with a TGase inhibitor, blocked EGF-stimulated cell migration and invasion. We show that EGF signaling through Ras and c-Jun N-terminal kinase is responsible for targeting TGase to the leading edges of cells and activating it. The requirement for EGF to properly localize and activate TGase can be circumvented by the expression of oncogenic Ras (G12V), whose ability to stimulate migration is also dependent on TGase. We further show that, in the highly aggressive breast cancer cell line MDAMB231, where EGF stimulation is unnecessary for migration and invasive activity, TGase is already at the leading edge and activated. These findings demonstrate that TGase plays a key role in cancer cell motility and invasiveness and represents a previously unappreciated participant in the EGF pathway that stimulates these processes in cancer cells.