A p38 MAPK regulated MEF2:β-catenin interaction enhances canonical Wnt signalling.

Canonical Wnt/beta-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 beta-catenin was implied but poorly understood. In the present study, we investigated potential cross talk between p38 MAPK and Wnt/beta-catenin signaling. Here we show that a loss of p38 MAPK alpha/beta function reduces beta-catenin nuclear accumulation in Wnt3a-stimulated primary vascular smooth muscle cells (VSMCs). Conversely, active p38 MAPK signaling increases beta-catenin nuclear localization and target gene activity in multiple cell types. Furthermore, the effect of p38 MAPK alpha/beta on beta-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 beta-catenin in multiple cell types and primary VSMCs that results in (i) increased beta-catenin nuclear retention, which is reversed by small interfering RNA (siRNA)-mediated MEF2 gene silencing; (ii) increased activation of MEF2 and Wnt/beta-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.