(Evi). The core component of the canonical pathway is the cadherin-interacting protein beta-catenin (Ctnnb1), which in the nucleus binds Lef/Hnf1a(Tcf1) transcription factors to turn on the expression of target genes. The consensus TCF cognate motif is: AGATCAAAGG. In the absence of the Wnt signal, the cytoplasmic beta-catenin is recruited to the 'destruction complex' with Axin and Apc and is phosphorylated on its N-terminal domain by Gsk3b and Csnk1a1 kinases. Axin acts as a scaffold bringing together Gsk3b and Csnk1a1, Apc and beta-catenin. The phosphorylated beta-catenin is recognized by the Btrc component of the E3 ubiquitin ligase complex and targeted for proteosomal degradation. The two kinases also posphorylate Apc and Axin; this enhances the association of Apc and Axin with beta-catenin, its phosphorylation and subsequent degradation. The interaction of Wnt ligands (19 members in mammals) with their frizzled (Fzd) receptors (10 members) and one of two Lrp co-receptors is antagonized and/or regulated by a number of secreted molecules. Wif1 binds to Wnt and sFRP members bind Wnt and Fzd. Members of the Dickkopf family of protein (Dkks) bind to the Lrp receptors; considered primarily inhibitors of the pathway - some members of the family might act as activators. Dkks are bound by Kremen receptors and the event potentiates the ability of Dkks to act as Wnt modulators. Additional inhibitors include Sost and Sostdc1 (Wise) that modulate the Wnt signal by interacting with Lrps. Several transmembrane antagonists have also been identified (not shown). The N-terminal cysteine-rich domains (CRD) of Fzd receptors mediate Wnt binding. A two-domain structure in Wnt, unrelated to known protein folds, is involved in binding the Fzd receptor; the two finger-like domains of Wnt, one of which contains the lipid moiety, grasp the CRD of Fzd (X-ray structure). Fzds are seven transmembrane receptors and evidence about the possible coupling to G-proteins is beginning to emerge. Additional agonists include Ndp (norrin) and the members of R-spondin (RSPOs) family. RSPO receptors are members of the leucine-rich repeat-containing, G protein-coupled receptor-related (LGRs), of which Lgr4/5 appear to be the main players. Ndp interacts with Lrp5 and Fzd4, the only Fzd that is a Ndp receptor; more recently, an interaction with Lrg4 has been documented. Their role is to potentiate the Wnt signaling by interacting with Lrp receptors or preventing the degradation of Lrp and Fzd by transmembrane RING finger ubiquitin ligases such as Znrf3 and Rnf43. Binding of Wnt to Fzd triggers the recruitment of Dvl (disheveled), followed by activation of beta catenin-dependent signaling. Phosphorylation of Lrps by Gsk3b and Csnk1g1 leads to axin binding; the interaction of axin with P-Lrp and possibly Dvl promotes the destabilization of the 'destruction complex'. Thereafter, beta-catenin can translocate to the nucleus where it displaces the transcriptional repressors of the Tle (Groucho) family from the Tcf/Lef effector complex and recruits a number of co-activators. Among target genes there are proliferation factors, the proto-oncogenic myc, components of the Wnt pathway. Altered Wnt signaling has been implicated in several conditions, primarily tumorigenesis and bone malformations. Hyperactive Wnt signaling is found in more than 90% of colorectal cancer (CRC). In addition to mutations in components of the pathway, aberrant splicing of these components has recently been associated with neoplasms, including CRC. To see the ontology report for Gviewer, annotations and download, click here click to see related GO term - GO:0060070 and KEGG map - map04310 and associated entry at Reactome - REACT_11045.1...(less)