The RhoU/Wrch1 Rho GTPase gene is a common transcriptional target of both the gp130/STAT3 and Wnt-1 pathways

Abstract

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.

Progesterone Decreases Levels of the Adhesion Protein E-Cadherin and Promotes Invasiveness of Steroid Receptor Positive Breast Cancers

“…5f, Online Resource 2). Consistent with these results, we found that E+R5020 treatment significantly increased mRNA levels of Wnt-1 and the Wnt-1-inducible gene RhoU [25] (Fig. 5g, h).…”

Rhou maintains the epithelial architecture and facilitates differentiation of the foregut endoderm

“…Canonical Wnt signalling contributes to the regulation of Rhou in the embryo, but Rhou is not a direct transcriptional target of -catenin, and is instead probably regulated via a JNK-mediated pathway (Schiavone et al, 2009;Tao et al, 2001). The results of this and other studies on the molecular mechanism of Rhou action highlight a likely connection between Wnt signalling, epithelial morphogenesis and the formation of organ primordia via Rhoumediated changes to the cytoskeleton that affect cell shape and mechanical properties (Fig.…”

Rho GTPases: Regulation and roles in cancer cell biology

“…98 Expression of RhoU and RhoV is increased at the transcriptional level by Wnt-1; and RhoU has also been shown to be induced by STAT3 and Notch1. 47,48,99,100 The N-and C-terminal domains of RhoU and RhoV are quite different from each other. The N-terminal domain of RhoU but not RhoV contains proline-rich domains that bind to the SH3 domains of Grb2 and Nck, 101 and its C-terminal domain is phosphorylated on tyrosine 254 by Src.…”