H-Ras is degraded by Wnt/beta-catenin signaling via beta-TrCP-mediated polyubiquitylation.

Ras is an important proto-protein that is regulated primarily by GDP/GTP exchange. Here, we report a novel regulatory mechanism whereby turnover of both endogenous and overexpressed H-Ras protein is controlled by beta-TrCP-mediated ubiquitylation, proteasomal degradation and the Wnt/beta-catenin signaling pathway. The interaction of H-Ras with the WD40 domain of beta-TrCP targeted H-Ras for polyubiquitylation and degradation. This process was stimulated by Axin or adenomatous polyposis coli (Apc), and was inhibited by Wnt3a. Ras-mediated cellular transformation was also inhibited by the expression of beta-TrCP and/or Axin. In vivo regulation of Ras stability by Wnt/beta-catenin signaling was determined via measurements of the status of Ras in the intestines of mice stimulated with recombinant Wnt3a by intravenous tail vein injection. The regulation of Ras stability by Wnt/beta-catenin signaling provides a mechanical basis for crosstalk between the Wnt/beta-catenin and the Ras-ERK pathways involved in transformation.