Scheme of the Wnt signaling pathway

Scheme of the Wnt signaling pathway. The Wnt glycoproteins are produced by the neighboring cells and secreted in a process that involves many components, such as a multiprotein retromer complex, and the multispanning transmembrane protein Wntless (Wls). The secreted Wnt ligands bind to the receptors of the seven-membrane-spanning Frizzled family and single-spanning LRP family. Secreted factors like secreted Frizzled-related proteins (sFRPs) bind to Wnts and block the interaction with Frizzled receptors. Dickkopf antagonizes Wnt signaling by blocking LRP receptors. Three main branches are activated downstream from the Wnt signals: canonical Wnt/β-catenin signaling (blue and red, in the center and on the left), and the noncanonical Jun kinase and Wnt/Ca2+ pathways (green and orange on the right). The central component of the canonical Wnt signaling is β-catenin (red). (Left and right) In the absence of the Wnt signals, β-catenin forms a stable complex with E-cadherin and participates in adherens junction formation. (Left) Excess β-catenin is captured by a destruction complex containing GSK3β, Axin1, Axin2/Conductin, and APC, where it gets N-terminally phosphorylated and, following ubiquitination by β-Trcp, targeted to proteosome-mediated degradation. In contrast, in the presence of the Wnt ligands, disassembly of the destruction complex occurs through phosphorylation of LRP5/6 by GSK3β and CK1α, and binding of Axin to LRP, thereby preventing β-catenin degradation. Free cytoplasmatic β-catenin can then enter the nucleus, where it forms a transcriptionally active complex with Tcf/Lef family of transcription factors, by replacing Grouchos from chromatin, and interacting with other coactivators like CBP, BCL9, and Pygopus. The three pathways branch at the level of Dishevelled (Dsh) protein. In the noncanonical Jun kinase pathway, Dsh via Daam1, is connected to downstream effectors, such as Rho, and regulates cytoskeletal organization and cell polarity. The Wnt/Ca2+pathway leads to the release of intracellular calcium, and involves activation of Phospholipase C (PLC) and protein kinase C (PKC). Ca2+ can activate Calmodulin-dependent protein kinase C (CaMKII), and Nemo-like kinase (NLK), and suppress canonical Wnt signaling.

Publication

Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of β-catenin in mice. (2008) Tamara Grigoryan, et al. Genes Dev. 2008 Sep 1;22(17):2308-2341. Figure: F1. All organisms Homo sapiens Mus musculus Drosophila melanogaster Danio rerio

Disease mentions