title: A p38 Mitogen-Activated Protein Kinase-Regulated Myocyte Enhancer Factor 2-β-Catenin Interaction Enhances Canonical Wnt Signaling.
abstract: Canonical Wnt/β-catenin signaling plays a major role in various biological contexts, such as embryonic development, cell proliferation, and cancer progression. Previously, a connection between p38 mitogen-activated protein kinase (MAPK) signaling and Wnt-mediated activation of β-catenin was implied but poorly understood. In the present study, we investigated potential cross talk between p38 MAPK and Wnt/β-catenin signaling. Here we show that a loss of p38 MAPK α/β function reduces β-catenin nuclear accumulation in Wnt3a-stimulated primary vascular smooth muscle cells (VSMCs). Conversely, active p38 MAPK signaling increases β-catenin nuclear localization and target gene activity in multiple cell types. Furthermore, the effect of p38 MAPK α/β on β-catenin activity is mediated through phosphorylation of a key p38 MAPK target, myocyte enhancer factor 2 (MEF2). Here we report a p38 MAPK-mediated, phosphorylation-dependent interaction between MEF2 and β-catenin in multiple cell types and primary VSMCs that results in (i) increased β-catenin nuclear retention, which is reversed by small interfering RNA (siRNA)-mediated MEF2 gene silencing; (ii) increased activation of MEF2 and Wnt/β-catenin target genes; and (iii) increased Wnt-stimulated cell proliferation. These observations provide mechanistic insight into a fundamental level of cross talk between p38 MAPK/MEF2 signaling and canonical Wnt signaling.
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada Muscle Health Research Centre (MHRC), York University, Toronto, Ontario, Canada Centre for Research in Biomolecular Interactions (CRBI), York University, Toronto, Ontario, Canada.
authors.forename: Saviz
authors.initials: S
authors.lastname: Ehyai
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada Muscle Health Research Centre (MHRC), York University, Toronto, Ontario, Canada Centre for Research in Biomolecular Interactions (CRBI), York University, Toronto, Ontario, Canada.
authors.forename: Mathew G
authors.initials: MG
authors.lastname: Dionyssiou
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada Muscle Health Research Centre (MHRC), York University, Toronto, Ontario, Canada Centre for Research in Biomolecular Interactions (CRBI), York University, Toronto, Ontario, Canada.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Gordon
authors.affiliation: Department of Chemistry, York University, Toronto, Ontario, Canada Centre for Research in Mass Spectrometry (CRMS), York University, Toronto, Ontario, Canada.
authors.forename: Declan
authors.initials: D
authors.lastname: Williams
authors.affiliation: Department of Chemistry, York University, Toronto, Ontario, Canada Centre for Research in Mass Spectrometry (CRMS), York University, Toronto, Ontario, Canada.
authors.forename: K W Michael
authors.initials: KW
authors.lastname: Siu
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada Muscle Health Research Centre (MHRC), York University, Toronto, Ontario, Canada Centre for Research in Biomolecular Interactions (CRBI), York University, Toronto, Ontario, Canada Centre for Research in Mass Spectrometry (CRMS), York University, Toronto, Ontario, Canada jmcderm@yorku.ca.
authors.forename: John C
authors.initials: JC
authors.lastname: McDermott
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D064326:MEF2 Transcription Factors / Q000378:metabolism*; D060066:Protein Interaction Maps; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D064326:MEF2 Transcription Factors; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases