CHARACTERIZATION OF WNT-1 AND WNT-2 INDUCED GROWTH ALTERATIONS AND SIGNALING PATHWAYS IN NIH3T3 FIBROBLASTS

Members of the Wnt family induce mouse mammary tumors and partially tr ansform mammary epithelial cells in culture. However, their mechanism of transformation remains to be elucidated. In NIH3T3 mouse embryo fib roblasts, a standard transformation model, Wnt-1 and Wnt-2 were shown to induce altered properties including increased saturation density an d growth in soft agar, Such cells also exhibited increased cell-cell a dhesiveness. However, unlike oncogenes such as PDGFB or ras, Wnt-1 and -2 failed to induce detectable transformed foci following transfectio n, and stable NIH3T3 transfectants lacked tumor forming capacity. Wnt- 1 and -2 transfectants exhibited increased uncomplexed, cytosolic beta -catenin, which was not observed with PDGFB, ras or erbB2 transfectant s. In transient transfection, Wnt-1 and -2 induced a rapid increase in cytosolic beta-catenin but no detectable increase in the phosphorylat ed activated forms of MAP kinase, In contrast, ras was a potent activa tor of MAP kinase but had no effect on free beta-catenin levels. These findings establish that both Wnt signaling and pattern of growth alte rations differ from those of oncogenes which activate proliferative si gnaling pathways in NIH3T3 cells.