title: Transglutaminase 2 as a novel activator of LRP6/β-catenin signaling.
abstract: 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.
authors.affiliation: Dept. of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: S
authors.initials: S
authors.lastname: Deasey
authors.forename: D
authors.initials: D
authors.lastname: Nurminsky
authors.forename: S
authors.initials: S
authors.lastname: Shanmugasundaram
authors.forename: F
authors.initials: F
authors.lastname: Lima
authors.forename: M
authors.initials: M
authors.lastname: Nurminskaya
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D011503:Transglutaminases / Q000378:metabolism*; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051176:beta Catenin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
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