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

• Published in: International journal of medical sciences 2013-01, Vol.10 (13), p.1888-1898
• Main Authors: Zhang, Wenwen, Zhang, Hongyu, Wang, Ning, Zhao, Chen, Zhang, Hongmei, Deng, Fang, Wu, Ningning, He, Yunfeng, Chen, Xian, Zhang, Junhui, Wen, Sheng, Liao, Zhan, Zhang, Qian, Zhang, Zhonglin, Liu, Wei, Yan, Zhengjian, Luu, Hue H, Haydon, Rex C, Zhou, Lan, He, Tong-Chuan
• Format: Article
• Language: English
• Subjects: Base Sequence; beta Catenin - metabolism; Blotting, Western; DNA Primers; Enzyme Activation; Fluorescent Antibody Technique; GTP-Binding Proteins - metabolism; HEK293 Cells; Humans; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Real-Time Polymerase Chain Reaction; Research Paper; Signal Transduction; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 1449-1907; 1449-1907
• DOI: 10.7150/ijms.6019

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.