The β-catenin signaling axis is critical for normal embryonic development and tissue homeostasis in adults. We have previously shown that extracellular enzyme transglutaminase 2 (TG2) activates β-catenin signaling in vascular smooth muscle cells (VSMCs). In this study, we provide several lines of evidence that TG2 functions as an activating ligand of the LRP5/6 receptors. Specifically, we show that TG2 synergizes with LRP6 in the activation of β-catenin-dependent gene expression in Cos-7 cells. Interfering with the LRP5/6 receptors attenuates TG2-induced activation of β-catenin in Cos-7 cells. Further, we show that TG2 binds directly to the extracellular domain of LRP6, which is also able to act as a substrate for TG2-mediated protein cross-linking. Furthermore, inhibitors of TG2 protein cross-linking quench the observed TG2-induced β-catenin activation, implicating protein cross-linking as a novel regulatory mechanism for this pathway. Together, our findings identify and characterize a new activating ligand of the LRP5/6 receptors and uncover a novel activity of TG2 as an agonist of β-catenin signaling, contributing to the understanding of diverse developmental events and pathological conditions in which transglutaminase and β-catenin signaling are implicated.
Keywords: APC; Adenomatosis Polyposis Coli; E. coli; ECM; Escherichia coli; Extracellular matrix; Frizzled; Fzd; GSK3; Glycogen Synthase Kinase 3; Guinea pig liver TG2; Human TG2; LRP5 or LRP6; LRP5/6; MEFs; Mouse embryonic fibroblasts; TG2; TGases; Tissue transglutaminase; Transglutaminases; Transglutaminsase 2; VSMCs; Vascular smooth muscle cells; gpTG2; hTG2; ß-catenin.
© 2013.