The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho-mediated actin reorganization
The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho-mediated actin reorganization
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DOI：
10.1038/sj.onc.1207759
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发表时间：
2004-07-22
期刊：
影响因子：
8
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
--
作者：
Miyoshi, K;Wakioka, T;Yoshimura, A
Sprouty和Sprouty相关蛋白Spred （Sprouty相关的Ena/血管扩张剂刺激磷酸化蛋白同源-1 （EVH1）结构域蛋白）抑制多种生长因子诱导的ras依赖性细胞外信号调节激酶（ERK）信号传导。由于Sprouty蛋白已被证明不仅抑制ERK激活，而且抑制细胞迁移，我们假设Sprouty也抑制细胞迁移。利用感染Spred1- sendai病毒载体的稳定高转移性LM8细胞，我们证明了Spred1抑制裸鼠LM8细胞的转移。Spred1过表达还能抑制细胞在体外对趋化因子CCL19和CCL21的迁移。我们还发现Spred1过表达溶解了肌动蛋白应激纤维。肌动蛋白重组需要EVH1结构域和c端sprouty相关结构域。Spred1和Spred2抑制组成型激活RhoA （V14RhoA）诱导的应激纤维形成和血清反应因子激活。Spred1与活化的RhoA结合，但不与cdc42和Rac结合。Spred1还抑制趋化因子诱导的RhoA活化和RhoA诱导的RhoA激酶活化。这些数据表明spred是rhoa介导的细胞运动和信号转导的关键调节因子。此外，我们的研究表明，诱导spred可能是一种防止癌细胞转移的新策略。
Sprouty and the Sprouty-related protein, Spred (Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology-1 (EVH1) domain-containing protein), inhibit Ras-dependent extracellular signal-regulated kinase (ERK) signaling induced by a variety of growth factors. Since Sprouty proteins have been shown to inhibit not only ERK activation but also cell migration, we postulated that Spreds also inhibit cellular migration. Using stably highly metastatic LM8 cells infected with the Spred1-Sendai virus vector, we demonstrated that Spred1 inhibits the metastasis of LM8 cells in nude mice. Spred1 overexpression also inhibited migration of cells in vitro in response to chemokines, CCL19 and CCL21. We also found that Spred1 overexpression dissolved actin-stress fibers. Both EVH1 domain and C-terminal Sprouty-related domain were required for actin reassembly. Spred1 and Spred2 suppressed constitutively activated RhoA (V14RhoA)-induced stress fiber formation and serum response factor activation. Spred1 bound to activated RhoA, but not cdc42 and Rac. Spred1 also inhibited chemokine-induced RhoA activation and active RhoA-induced Rho-kinase activation. These data suggest that Spreds are key regulators of RhoA-mediated cell motility and signal transduction. Furthermore, our study suggests that the induction of Spreds could be a novel strategy for preventing cancer cell metastasis.