regulation of canonical Wnt signaling pathway

Definition

Target type: biologicalprocess

Any process that modulates the rate, frequency, or extent of the Wnt signaling pathway through beta-catenin, the series of molecular signals initiated by binding of a Wnt protein to a frizzled family receptor on the surface of the target cell, followed by propagation of the signal via beta-catenin, and ending with a change in transcription of target genes. [GOC:dph, GOC:sdb_2009, GOC:tb]

The canonical Wnt signaling pathway plays a critical role in embryonic development, tissue homeostasis, and adult stem cell maintenance. It is a complex and highly regulated pathway, involving multiple steps and proteins. The pathway is activated when Wnt proteins bind to their cognate receptors, Frizzled (Fzd) and LRP5/6. This binding triggers a cascade of events leading to the stabilization of β-catenin and its translocation into the nucleus, where it acts as a transcription factor to activate target genes.

In the absence of Wnt ligands, β-catenin is kept at low levels in the cytoplasm due to the activity of the destruction complex. The destruction complex comprises several proteins: Axin, APC (Adenomatous polyposis coli), GSK3β (Glycogen synthase kinase 3β), and CK1α (Casein kinase 1 alpha). These proteins work together to phosphorylate β-catenin, marking it for ubiquitination and degradation by the proteasome.

Upon Wnt ligand binding, the destruction complex is disrupted. LRP5/6, the co-receptor for Wnt, recruits Dishevelled (Dvl) to the membrane. Dvl is a scaffolding protein that activates several downstream pathways, including the inhibition of GSK3β. This inhibition prevents β-catenin phosphorylation and subsequent degradation.

In addition to GSK3β inhibition, Wnt signaling also promotes the recruitment of β-catenin to the plasma membrane by interacting with a protein called Axin. This interaction sequesters Axin away from the destruction complex, further stabilizing β-catenin.

With its levels increased, β-catenin translocates to the nucleus, where it binds to the TCF/LEF (T-cell factor/lymphoid enhancer factor) family of transcription factors. This complex activates the transcription of target genes, which are involved in cell proliferation, differentiation, survival, and migration.

The Wnt signaling pathway is tightly regulated by various mechanisms, including feedback loops and inhibitors. One example of a feedback loop is the Wnt-induced expression of DKK1 (Dickkopf-1), a secreted inhibitor of the Wnt pathway. DKK1 binds to LRP5/6 and prevents Wnt from activating the pathway.

The Wnt signaling pathway is highly susceptible to dysregulation, which can lead to various diseases, including cancer, developmental defects, and bone diseases. Understanding the intricate regulation of this pathway is crucial for developing new therapeutic strategies for these conditions.'
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Proteins (6)

Compounds (124)