A p38 Mitogen-Activated Protein Kinase-Regulated Myocyte Enhancer Factor 2–β-Catenin Interaction Enhances Canonical Wnt Signaling

Abstract

Canonical Wnt/?-catenin signaling plays a major role in various biological contexts, such as embryonic development, cell prolif- eration, and cancer progression. Previously, a connection between p38 mitogen-activated protein kinase (MAPK) signaling and Wnt-mediated activation of ?-catenin was implied but poorly understood. In the present study, we investigated potential cross talk between p38MAPKand Wnt/?-catenin signaling. Here we show that a loss of p38MAPK?/?function reduces?-catenin nuclear accumulation in Wnt3a-stimulated primary vascular smooth muscle cells (VSMCs). Conversely, active p38MAPKsig- naling increases?-catenin nuclear localization and target gene activity in multiple cell types. Furthermore, the effect of p38 MAPK?/?on?-catenin activity is mediated through phosphorylation of a key p38MAPKtarget, myocyte enhancer factor 2 (MEF2). Here we report a p38 MAPK-mediated, phosphorylation-dependent interaction between MEF2 and ?-catenin in multi- ple cell types and primary VSMCs that results in (i) increased ?-catenin nuclear retention, which is reversed by small interfering RNA(siRNA)-mediated MEF2 gene silencing; (ii) increased activation of MEF2 and Wnt/?-catenin target genes; and (iii) in- creased 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.