A computational cell-based model of lumen formation during angiogenesis

Classical Wnt-mediated β-catenin signaling entails disruption of the destruction complex, sequestering of CK1 and GSK-3, thereby preventing the phosphorylation and subsequent degradation of -catenin. Chronic activation of Wnt/-catenin signaling is found in a variety of human malignancies including melanoma, colorectal and hepatocellular carcinomas. Interestingly, expression of the HCMV-encoded chemokine receptor US28 in intestinal epithelial cells promotes intestinal neoplasia in transgenic mice, which is associated with increased activation of the catenin pathway. In this study we show that this viral receptor leads to activation of -catenin and enhanced β-catenin-dependent transcription through a distinct and novel mechanism. Analysis of the US28 signalosome and inhibitor studies indicates the involvement of the Rho-ROCK pathway and a prominent role for 14-3-3 proteins and the 14-3-3 target protein, Chibby (Cby), culminating in activation of active (nonphosphorylated) β-catenin. The non-classical activation of the βcatenin signal transduction pathway by this viral chemokine receptor may provide alternative regulation of this pathway, crucial in development of colon cancer and of importance in HCMV-associated diseases. Quantitative dissection of the modes of growth inhibition by weak organic acids