title: Modulation of β-catenin signaling by the inhibitors of MAP kinase, tyrosine kinase, and PI3-kinase pathways.
abstract: 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.
authors: 1. Ministry of Education Key Laboratory of Diagnostic Medicine and School of Clinical Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China; ; 2. Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA; ; 3. Department of Laboratory Medicine of the Affiliated Hospital, Bingzhou Medical University, Yantai, Shandong, China;
authors: Wenwen
authors: W
authors: Zhang
authors: Hongyu
authors: H
authors: Zhang
authors: Ning
authors: N
authors: Wang
authors: Chen
authors: C
authors: Zhao
authors: Hongmei
authors: H
authors: Zhang
authors: Fang
authors: F
authors: Deng
authors: Ningning
authors: N
authors: Wu
authors: Yunfeng
authors: Y
authors: He
authors: Xian
authors: X
authors: Chen
authors: Junhui
authors: J
authors: Zhang
authors: Sheng
authors: S
authors: Wen
authors: Zhan
authors: Z
authors: Liao
authors: Qian
authors: Q
authors: Zhang
authors: Zhonglin
authors: Z
authors: Zhang
authors: Wei
authors: W
authors: Liu
authors: Zhengjian
authors: Z
authors: Yan
authors: Hue H
authors: HH
authors: Luu
authors: Rex C
authors: RC
authors: Haydon
authors: Lan
authors: L
authors: Zhou
authors: Tong-Chuan
authors: TC
authors: He
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate
keywords: G protein; MEK kinase; PI3 kinase; Wnt signaling.; protein kinase C; tumorigenesis; tyrosine phosphorylation; β-catenin