Research ArticleCancer

Ras Stabilization Through Aberrant Activation of Wnt/β-Catenin Signaling Promotes Intestinal Tumorigenesis

Sci. Signal.  10 Apr 2012:
Vol. 5, Issue 219, pp. ra30
DOI: 10.1126/scisignal.2002242

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Blocking Ras Degradation in Colon Cancer

Both the Wnt/β-catenin pathway and the Ras-activated mitogen-activated protein kinase (MAPK) pathway can contribute to cancer. Jeong et al. report an interaction between these two pathways through the β-catenin destruction complex and the E3 ubiquitin ligase adaptor β-TrCP. Ras was phosphorylated by glycogen synthase kinase 3β, a component of the β-catenin destruction complex, and this enabled the phosphorylation-dependent recruitment of β-TrCP, which increased ubiquitin- and proteasome-mediated degradation of Ras, thereby providing a brake on Ras-mediated activation of the MAPK pathway. Conditions that compromised the function of the destruction complex, such as the presence of Wnt or genetic mutations or deficiency in components of the destruction complex, stabilized Ras and increased MAPK pathway activity. The importance of this regulatory crosstalk was verified in colon cancer samples from patients and mouse models of colon cancer, suggesting that targeting both the hyperactive Wnt pathway and the Ras pathway may be an effective combination therapy.