The RhoU/Wrch1 Rho GTPase gene is a common transcriptional target of both the gp130/STAT3 and Wnt-1 pathways.
The RhoU/Wrch1 Rho GTPase gene is a common transcriptional target of both the gp130/STAT3 and Wnt-1 pathways.
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DOI：
10.1042/bj20090061
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发表时间：
2009-06-26
期刊：
影响因子：
--
通讯作者：
Poli V
中科院分区：
文献类型：
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作者：
Schiavone D;Dewilde S;Vallania F;Turkson J;Di Cunto F;Poli V
STAT3（信号换能器和转录激活因子3）是一种由细胞因子、生长因子和癌基因激活的转录因子，其活性是多种原发性肿瘤和肿瘤细胞系细胞存活/增殖所必需的。在其对肿瘤细胞的多种作用中，最突出的是刺激细胞迁移和转移，但其作用机制尚未完全明确。RhoU/Wrch1 （Wnt-responsive Cdc42 homologue）是一种非典型的Rho GTPase，被认为与GTP组成性结合。RhoU首先被确定为wnt -1诱导的mRNA，随后被证明通过刺激丝状足形成和应力纤维溶解作用于肌动蛋白细胞骨架。此外，最近还显示，它可以定位于局灶粘连和src诱导的足质体，并增强细胞迁移。RhoU在乳腺上皮细胞中的过度表达刺激静止细胞重新进入细胞周期，并在形态学上表型上发生wnt -1依赖性转化。在本研究中，我们发现wnt -1介导的RhoU诱导发生在转录水平。此外，我们证明了gp130细胞因子也可以通过STAT3诱导RhoU，并且我们在小鼠RhoU启动子上鉴定了两个功能STAT3结合位点。Wnt-1诱导RhoU与β-catenin无关，但不涉及STAT3。相反，它是由Wnt/平面细胞极性通路通过JNK （c-Jun n -末端激酶）的激活介导的。因此，所谓的非规范Wnt通路和STAT3都能够诱导RhoU，这反过来可能参与介导它们对细胞迁移的影响。
STAT3 (signal transducer and activator of transcription 3) is a transcription factor activated by cytokines, growth factors and oncogenes, whose activity is required for cell survival/proliferation of a wide variety of primary tumours and tumour cell lines. Prominent among its multiple effects on tumour cells is the stimulation of cell migration and metastasis, whose functional mechanisms are however not completely characterized. RhoU/Wrch1 (Wnt-responsive Cdc42 homologue) is an atypical Rho GTPase thought to be constitutively bound to GTP. RhoU was first identified as a Wnt-1-inducible mRNA and subsequently shown to act on the actin cytoskeleton by stimulating filopodia formation and stress fibre dissolution. It was in addition recently shown to localize to focal adhesions and to Src-induced podosomes and enhance cell migration. RhoU overexpression in mammary epithelial cells stimulates quiescent cells to re-enter the cell cycle and morphologically phenocopies Wnt-1-dependent transformation. In the present study we show that Wnt-1-mediated RhoU induction occurs at the transcriptional level. Moreover, we demonstrate that RhoU can also be induced by gp130 cytokines via STAT3, and we identify two functional STAT3-binding sites on the mouse RhoU promoter. RhoU induction by Wnt-1 is independent of β-catenin, but does not involve STAT3. Rather, it is mediated by the Wnt/planar cell polarity pathway through the activation of JNK (c-Jun N-terminal kinase). Both the so-called non-canonical Wnt pathway and STAT3 are therefore able to induce RhoU, which in turn may be involved in mediating their effects on cell migration.