Mixed lineage kinase 3 modulates β-catenin signaling in cancer cells

Ramesh P. Thylur, Subramanian Senthivinayagam, Edward M. Campbell, Velusamy Rangasamy, Nithyananda Thorenoor, Gautam Sondarva, Suneet Mehrotra, Prajna Mishra, Erin Zook, Phong T. Le, Ajay Rana, Basabi Rana

Research output: Contribution to journalArticle

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37470-37482
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number43
DOIs
StatePublished - Oct 28 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Thylur, R. P., Senthivinayagam, S., Campbell, E. M., Rangasamy, V., Thorenoor, N., Sondarva, G., Mehrotra, S., Mishra, P., Zook, E., Le, P. T., Rana, A., & Rana, B. (2011). Mixed lineage kinase 3 modulates β-catenin signaling in cancer cells. Journal of Biological Chemistry, 286(43), 37470-37482. https://doi.org/10.1074/jbc.M111.298943