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Int J Med Sci. 2013 Nov 25;10(13):1888-98. doi: 10.7150/ijms.6019. eCollection 2013.

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

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  • 11. 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;

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.

KEYWORDS:

G protein; MEK kinase; PI3 kinase; Wnt signaling.; protein kinase C; tumorigenesis; tyrosine phosphorylation; β-catenin

PMID:
24324366
PMCID:
PMC3856380
DOI:
10.7150/ijms.6019
[PubMed - indexed for MEDLINE]
Free PMC Article
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