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• W2088953459 abstract "Expression of β-catenin is strictly regulated in normal cells via the glycogen synthase kinase 3β (GSK3β)- adenomatous polyposis coli-axin-mediated degradation pathway. Mechanisms leading to inactivation of this pathway (example: activation of Wnt/β-catenin signaling or mutations of members of the degradation complex) can result in β-catenin stabilization and activation of β-catenin/T-cell factor (TCF) signaling. β-Catenin-mediated cellular events are diverse and complex. A better understanding of the cellular signaling networks that control β-catenin pathway is important for designing effective therapeutic strategies targeting this axis. To gain more insight, we focused on determining any possible cross-talk between β-catenin and mixed lineage kinase 3 (MLK3), a MAPK kinase kinase member. Our studies indicated that MLK3 can induce β-catenin expression via post-translational stabilization in various cancer cells, including prostate cancer. This function of MLK3 was dependent on its kinase activity. MLK3 can interact with β-catenin and phosphorylate it in vitro. Overexpression of GSK3β-WT or the S9A mutant was unable to antagonize MLK3-induced stabilization, suggesting this to be independent of GSK3β pathway. Surprisingly, despite stabilizing β-catenin, MLK3 inhibited TCF transcriptional activity in the presence of both WT and S37A β-catenin. These resulted in reduced expression of β-catenin/TCF downstream targets Survivin and myc. Immunoprecipitation studies indicated that MLK3 did not decrease β-catenin/TCF interaction but promoted interaction between β-catenin and KLF4, a known repressor of β-catenin/TCF transcriptional activity. In addition, co-expression of MLK3 and β-catenin resulted in significant G(2)/M arrest. These studies provide a novel insight toward the regulation of β-catenin pathway, which can be targeted to control cancer cell proliferation, particularly those with aberrant activation of β-catenin signaling." @default.
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• W2088953459 date "2011-10-01" @default.
• W2088953459 modified "2023-10-15" @default.
• W2088953459 title "Mixed Lineage Kinase 3 Modulates β-Catenin Signaling in Cancer Cells" @default.
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• W2088953459 doi "https://doi.org/10.1074/jbc.m111.298943" @default.
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