The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca²⁺ pathway to antagonize Wnt/β-catenin signaling

Wnt signaling controls a variety of developmental processes. The canonical Wnt/β-catenin pathway functions to stabilize β-catenin, and the noncanonical Wnt/Ca²⁺ pathway activates Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). In addition, the Wnt/Ca²⁺ pathway activated by Wnt-5a antagonizes the Wnt/β-catenin pathway via an unknown mechanism. The mitogen-activated protein kinase (MAPK) pathway composed of TAK1 MAPK kinase kinase and NLK MAPK also negatively regulates the canonical Wnt/β-catenin signaling pathway. Here we show that activation of CaMKII induces stimulation of the TAK1-NLK pathway. Overexpression of Wnt-5a in HEK293 cells activates NLK through TAK1. Furthermore, by using a chimeric receptor (β₂AR-Rfz-2) containing the ligand-binding and transmembrane segments from the β₂-adrenergic receptor (β₂AR) and the cytoplasmic domains from rat Frizzled-2 (Rfz-2), stimulation with the β-adrenergic agonist isoproterenol activates activities of endogenous CaMKII, TAK1, and NLK and inhibits β-catenin-induced transcriptional activation. These results suggest that the TAK1-NLK MAPK cascade is activated by the noncanonical Wnt-5a/Ca²⁺ pathway and antagonizes canonical Wnt/β-catenin signaling.