Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism.
Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism.
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DOI：
10.1083/jcb.201005141
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发表时间：
2010-08-09
期刊：
影响因子：
--
通讯作者：
Katoh H
中科院分区：
文献类型：
--
作者：
Hiramoto-Yamaki N;Takeuchi S;Ueda S;Harada K;Fujimoto S;Negishi M;Katoh H
epexin4是一种rhog特异性鸟嘌呤核苷酸交换因子，可与乳腺癌细胞中的EphA2受体相互作用。EphA2是Eph受体家族的一员，在包括乳腺癌在内的多种人类癌症中经常过表达，并独立于配体ephrin刺激促进癌细胞的运动和侵袭。在本研究中，我们在乳腺癌细胞中鉴定出Ephexin4是与EphA2相互作用的RhoG的鸟嘌呤核苷酸交换因子（GEF），并通过敲除和挽救实验表明，Ephexin4作用于EphA2的下游，通过激活RhoG促进不依赖配体的乳腺癌细胞向表皮生长因子的迁移和侵袭。RhoG的激活会招募其效应物ELMO2和Rac GEF Dock4，在迁移的乳腺癌细胞中富含接触蛋白的突起的尖端与EphA2形成复合物。此外，dock4介导的Rac激活是乳腺癌细胞迁移所必需的。我们的发现揭示了EphA2和Rac激活之间的一种新的联系，这种联系有助于乳腺癌细胞的运动和侵袭性。
Ephexin4 is a RhoG-specific guanine nucleotide exchange factor that interacts with the EphA2 receptor in breast cancer cells. EphA2, a member of the Eph receptor family, is frequently overexpressed in a variety of human cancers, including breast cancers, and promotes cancer cell motility and invasion independently of its ligand ephrin stimulation. In this study, we identify Ephexin4 as a guanine nucleotide exchange factor (GEF) for RhoG that interacts with EphA2 in breast cancer cells, and knockdown and rescue experiments show that Ephexin4 acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. The activation of RhoG recruits its effector ELMO2 and a Rac GEF Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells. In addition, the Dock4-mediated Rac activation is required for breast cancer cell migration. Our findings reveal a novel link between EphA2 and Rac activation that contributes to the cell motility and invasiveness of breast cancer cells.
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