Dual-specificity phosphatases are targets of the Wnt/ß-catenin pathway and candidate mediators of ß-catenin/Ras signaling interactions.

ABSTRACT

The Wnt/ß-catenin and the Ras/mitogen-activated protein kinase (MAPK) pathways play important roles in cancer development. Both pathways have been studied discretely, but the mechanisms of possible crosstalk are still not fully understood. We have previously shown that ß-catenin and MAPK signaling interfere with each other in murine liver in vivo and in vitro. Here, we show that dual specificity phosphatases (Dusps) 6 and 14, known to play an essential role in regulating MAPK pathway activity via feedback mechanisms, are up-regulated by activation of ß-catenin in murine liver cells, whereas the epidermal growth factor receptor, an upstream effector in the Ras/MAPK cascade, is down-regulated by ß-catenin. In addition, we identified a ß-catenin-binding site within the Dusp6 promoter, which is responsible for the activation of the promoter by ß-catenin signaling, and demonstrated reduced inducibility of MAPK signaling in cultured mouse hepatoma cells following ß-catenin activation. Thus, ß-catenin is able to inhibit activation of the Egfr/Ras/MAPK signaling cascade, both at the receptor level and by interfering with MAPK activity via Dusps.