Modulation of β-catenin signaling by the inhibitors of MAP kinase, tyrosine kinase, and PI3-kinase pathways.

Aberrant activation of β-catenin signaling plays an important role in human tumorigenesis. However, molecular mechanisms behind the β-catenin signaling deregulation are mostly unknown because genetic alterations in this pathway only account for a small fraction of tumors. Here, we investigator if other major pathways can regulate β-catenin signaling activity. By employing a panel of chemical activators and/or inhibitors of several cellular signaling pathways, we assess these modulators' effects on luciferase reporter driven by β-catenin/TCF4-responsive elements. We find that lithium-stimulated β-catenin activity is synergistically enhanced by protein kinase C activator PMA. However, β-catenin-regulated transcriptional (CRT) activity is significantly inhibited by casein kinase II inhibitor DRB, MEK inhibitor PD98059, G-proteins and their receptor uncoupling agent suramin, protein tyrosine kinase inhibitor genistein, and PI-3 kinase inhibitor wortmannin, suggesting that these cellular pathways may participate in regulating β-catenin signaling. Interestingly, the Ca⁺⁺/calmodulin kinase II inhibitor HDBA is shown to activate β-catenin activity at low doses. Furthermore, Wnt3A-stimulated and constitutively activated CRT activities, as well as the intracellular accumulation of β-catenin protein in human colon cancer cells, are effectively suppressed by PD98059, genistein, and wortmannin. We further demonstrate that EGF can activate TCF4/β-catenin activity and induce the tyrosine phosphorylation of β-catenin protein. Thus, our results should provide important insights into the molecular mechanisms underlying Wnt/β-catenin activation. This knowledge should facilitate our efforts to develop efficacious and novel therapeutics by targeting these pathways.