title: Mixed lineage kinase 3 modulates β-catenin signaling in cancer cells.
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.
authors: Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Loyola University Chicago, Maywood, Ilinois 60153, USA.
authors: Ramesh P
authors: RP
authors: Thylur
authors: Subramanian
authors: S
authors: Senthivinayagam
authors: Edward M
authors: EM
authors: Campbell
authors: Velusamy
authors: V
authors: Rangasamy
authors: Nithyananda
authors: N
authors: Thorenoor
authors: Gautam
authors: G
authors: Sondarva
authors: Suneet
authors: S
authors: Mehrotra
authors: Prajna
authors: P
authors: Mishra
authors: Erin
authors: E
authors: Zook
authors: Phong T
authors: PT
authors: Le
authors: Ajay
authors: A
authors: Rana
authors: Basabi
authors: B
authors: Rana
mesh_terms: D019943:Amino Acid Substitution; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D016195:G2 Phase / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D000077022:Survivin; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D051034:Inhibitor of Apoptosis Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D020930:MAP Kinase Kinase Kinases; D009363:Neoplasm Proteins; D000077022:Survivin; D051820:TCF Transcription Factors; D051176:beta Catenin; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C107489:BIRC5 protein, human; C000715467:KLF4 protein, human; C000605506:GSK3B protein, human