WNT/β-catenin Signaling

Wnt proteins are a family of extracellular growth factors involved in various aspects of development like cell differentiation, cell polarity and cell proliferation.Wnt proteins are secreted glycoproteins that bind to frizzled seven-transmembrane span receptors, which may be coupled to G proteins. Members of the low-density lipoprotein receptor-related protein family- LRP5/6 act as essential co-receptors of Wnt ligands and are required for β-catenin-dependent signal transduction. Dickkopf (Dkk) along with Kremen antagonizes the LRP co receptor by inducing its endocytosis.Wnt signaling leads to the stabilization of cytosolic β-catenin which then translocates to the nucleus and facilitates the transcription of Wnt target genes. In the absence of Wnt ligands, β-catenin is phosphorylated sequentially by Casein kinase I (CKI) and then Glycogen synthase kinase 3β (GSK3β). The phosphorylation of β-catenin occurs in a multiprotein complex whose members include the scaffold protein Axin and the tumor suppressor adenomatous polyposis coli protein (APC). Phosphorylation of β-catenin triggers its ubiquitylation by beta-transducin repeat containing protein (βTrCP) and degradation in proteasomes. β-Catenin degradation is modulated by the serine/threonine protein phosphatase PP2A.In the presence of Wnts, β-catenin phosphorylation by GSK3β is inhibited by disheveled (Dsh) and GSK3 binding protein (GBP). Dsh activity is modulated by the kinase PAR1. The stabilized β-catenin then translocates to the nucleus, where it activates transcription along with T cell activation factor (TCF), the histone acetyl transferase CBP and B-cell lymphoma 9 (BCL9). In the absence of β-catenin certain TCFs repress transcription by interacting with the co repressors bound to histone deacetylase (HDAC). Several factors can regulate Wnt induced transcription e.g. NEMO-like kinase (NLK), Sox proteins and retinoic acid receptor (RAR).This pathway highlights the important components of Wnt/β-catenin signal transduction.