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首页> 外文期刊>Cellular Physiology and Biochemistry >TGFβ-induced early activation of the small GTPase RhoA is smad2/3-independent and involves Src and the guanine nucleotide exchange factor Vav2
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TGFβ-induced early activation of the small GTPase RhoA is smad2/3-independent and involves Src and the guanine nucleotide exchange factor Vav2

机译：TGFβ诱导的小GTPase RhoA的早期激活不依赖smad2 / 3，涉及Src和鸟嘌呤核苷酸交换因子Vav2

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TGFβ has been shown to induce short-and long-term actin reorganization controlled by Rho-GTPase signaling. A number of direct Smad target genes, rapidly activated by TGFβ, have been previously reported to control the long-term Rho activation and actin reorganization. However, the molecular mechanisms that regulate the prompt stimulation of Rho GTPases by TGFβ remain unknown. In the present study we report that TGFβ rapidly stimulated RhoA and RhoB activation in JEG3 choriocarcinoma cells that lack endogenous Smad3. Inhibition of Smad2 expression via siRNA-mediated silencing or by blocking its phosphorylation using the TβRI inhibitor SB431542 did not prevent the early RhoA/B activation by TGFβ indicating that this effect is Smad2/3-independent. Pre-treatment of the cells with the general tyrosine kinase inhibitor Genistein blocked the TGFβ-induced early RhoA activation. In line with this finding, TGFβ-stimulation resulted in a quick activation of the non-receptor tyrosine kinase Src, followed by activation of the guanine nucleotide exchange factor (GEF) Vav2. Inhibition of Src kinase by the selective inhibitor of the Src family tyrosine kinases PP2 totally blocked the early TGFβ-induced RhoA activation. Similarly, Vav2 silencing via siRNA reduced the TGFβ-induced RhoA activation implying that the rapid Src/Vav2 stimulation was effective in regulating RhoA activation. Our present findings provide for the first time a clear evidence for the role of Src and Vav2-GEF in the early Smad2/3-independent Rho activation by TGFβ.
机译：已经证明TGFβ诱导受Rho-GTPase信号传导控制的短期和长期肌动蛋白重组。先前已经报道了许多由TGFβ快速激活的直接Smad靶基因，它们可控制Rho的长期激活和肌动蛋白的重组。然而，调节TGFβ迅速刺激Rho GTPases的分子机制仍然未知。在本研究中，我们报道了TGFβ在缺乏内源性Smad3的JEG3绒毛膜癌细胞中快速刺激RhoA和RhoB活化。通过siRNA介导的沉默或通过使用TβRI抑制剂SB431542阻止其Smad2磷酸化来抑制Smad2表达，不能阻止TGFβ早期激活RhoA / B，这表明该作用不依赖Smad2 / 3。用一般的酪氨酸激酶抑制剂金雀异黄素对细胞进行预处理可以阻断TGFβ诱导的早期RhoA激活。与该发现一致，TGFβ的刺激导致非受体酪氨酸激酶Src的快速活化，随后鸟嘌呤核苷酸交换因子（GEF）Vav2的活化。 Src家族酪氨酸激酶PP2的选择性抑制剂对Src激酶的抑制作用完全阻断了早期TGFβ诱导的RhoA激活。类似地，通过siRNA的Vav2沉默降低了TGFβ诱导的RhoA激活，这意味着快速Src / Vav2刺激可有效调节RhoA激活。我们目前的发现首次为Src和Vav2-GEF在TGFβ早期Smad2 / 3独立的Rho激活中的作用提供了明确的证据。

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