The RhoU/Wrch1 Rho GTPase gene is a common transcriptional target of both the gp130/Stat3 and Wnt-1 pathways
Résumé
Stat3 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 tumors and tumor cell lines. Prominent among its multiple effects on tumor cells is the stimulation of cell migration and metastasis, whose functional mechanisms are however not completely characterized. RhoU/Wrch1 (Wnt-responsive Cdc42 homolog) 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 fibers 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. Here 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 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. 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.
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