Rho GTPase activity modulates Wnt3a/b-catenin signaling

• Published in: Cellular signalling 2009-11, Vol.21 (11), p.1559-1568
• Main Authors: Rossol-Allison, Jessica, Stemmle, Laura N, Swenson-Fields, Katherine I, Kelly, Patrick, Fields, Patrick E, McCall, Shannon J, Casey, Patrick J, Fields, Timothy A
• Format: Article
• Language: English
• ISSN: 0898-6568
• DOI: 10.1016/j.cellsig.2009.05.010

Wnt proteins constitute a family of secreted signaling molecules that regulate highly conserved pathways essential for development and, when aberrantly activated, drive oncogenesis in a number of human cancers. A key feature of the most widely studied Wnt signaling cascade is the stabilization of cytosolic b-catenin, resulting in b-catenin nuclear translocation and transcriptional activation of multiple target genes. In addition to this canonical, b-catenin-dependent pathway, Wnt3A has also been shown to stimulate RhoA GTPase. While the importance of activated Rho to non-canonical Wnt signaling is well appreciated, the potential contribution of Wnt3A-stimulated RhoA to canonical b-catenin-dependent transcription has not been examined and is the focus of this study. We find that activated Rho is required for Wnt3A-stimulated osteoblastic differentiation in C3H10T1/2 mesenchymal stem cells, a biological phenomenon mediated by stabilized b-catenin. Using expression microarrays and real-time RT-PCR analysis, we show that Wnt3A- stimulated transcription of a subset of target genes is Rho-dependent, indicating that full induction of these Wnt targets requires both b-catenin and Rho activation. Significantly, neither b-catenin stabilization nor nuclear translocation stimulated by Wnt3A is affected by inhibition or activation of RhoA. These findings identify Rho activation as a critical element of the canonical Wnt3A-stimulated, b-catenin-dependent transcriptional program.