GEP100/Arf6 is required for epidermal growth factor-induced ERK/Rac1 signaling and cell migration in human hepatoma HepG2 cells.
GEP100/Arf6 is required for epidermal growth factor-induced ERK/Rac1 signaling and cell migration in human hepatoma HepG2 cells.
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GEP100/Arf6 是人肝癌 HepG2 细胞中表皮生长因子诱导的 ERK/Rac1 信号传导和细胞迁移所必需的
DOI：
10.1371/journal.pone.0038777
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Hu Z;Du J;Yang L;Zhu Y;Yang Y;Zheng D;Someya A;Gu L;Lu X
背景：表皮生长因子(EGF)信号转导与肝癌细胞的侵袭转移有关。然而，EGF诱导肝癌细胞运动的信号通路尚不清楚。方法/主要发现我们发现EGF对人肝癌细胞HepG2的迁移有剂量依赖性的刺激作用，在10 ng/mL时作用最大。此外，EGF增加了Arf6的活性，并且Arf6 T27N(显性负Arf6突变体)的异位表达在很大程度上取消了EGF诱导的细胞迁移。用GEP100 siRNA或GEP100同源(PH)结构域缺失突变体GEP100-PH阻断GEP100，可阻断EGF诱导的Arf6活性和细胞迁移。EGF还可增加ERK和rac1的活性。异位表达GEP100 siRNA、GEP100-PH或Arf6-T27N可抑制EGF诱导的ERK和rac1活性。此外，用其抑制剂U0126阻断ERK信号通路可显著抑制EGF诱导的rac1活化和细胞迁移，异位表达失活突变形式的rac1(rac1-T17N)也可显著抑制EGF诱导的细胞迁移。结论/意义综上所述，本研究强调了GEP100的PH结构域及其调控的Arf6/ERK/rac1信号通路在EGF诱导的肝癌细胞迁移中的作用。这些发现可能为设计基于抑制肝癌转移的新的治疗方法提供理论依据。
Background Epidermal growth factor (EGF) signaling is implicated in the invasion and metastasis of hepatoma cells. However, the signaling pathways for EGF-induced motility of hepatoma cells remain undefined. Methodology/Principal Findings We found that EGF dose-dependently stimulated the migration of human hepatoma cells HepG2, with the maximal effect at 10 ng/mL. Additionally, EGF increased Arf6 activity, and ectopic expression of Arf6 T27N, a dominant negative Arf6 mutant, largely abolish EGF-induced cell migration. Blocking GEP100 with GEP100 siRNA or GEP100-△PH, a pleckstrin homology (PH) domain deletion mutant of GEP100, blocked EGF-induced Arf6 activity and cell migration. EGF also increased ERK and Rac1 activity. Ectopic expression GEP100 siRNA, GEP100-△PH, or Arf6-T27N suppressed EGF-induced ERK and Rac1 activity. Furthermore, blocking ERK signaling with its inhibitor U0126 remarkably inhibited both EGF-induced Rac1 activation as well as cell migration, and ectopic expression of inactive mutant form of Rac1 (Rac1-T17N) also largely abolished EGF-induced cell migration. Conclusions/Significance Taken together, this study highlights the function of the PH domain of GEP100 and its regulated Arf6/ERK/Rac1 signaling cascade in EGF-induced hepatoma cell migration. These findings could provide a rationale for designing new therapy based on inhibition of hepatoma metastasis.
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影响因子：
3.7
作者：
Hashimoto A;Hashimoto S;Ando R;Noda K;Ogawa E;Kotani H;Hirose M;Menju T;Morishige M;Manabe T;Toda Y;Ishida S;Sabe H
通讯作者：
Sabe H
DOI：
10.1186/1478-811x-8-23
发表时间：
2010-09-07
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Parri M;Chiarugi P
通讯作者：
Chiarugi P
使用纳米制造的神经探针进行多重、高密度电生理学。
影响因子：
3.7
作者：
Du J;Blanche TJ;Harrison RR;Lester HA;Masmanidis SC
通讯作者：
Masmanidis SC
影响因子：
9.2
作者：
Dunphy, JL;Moravec, R;Casanova, JE
通讯作者：
Casanova, JE
影响因子：
11.2
作者：
Muralidharan-Chari V;Hoover H;Clancy J;Schweitzer J;Suckow MA;Schroeder V;Castellino FJ;Schorey JS;D'Souza-Schorey C
通讯作者：
D'Souza-Schorey C