negative regulation of canonical Wnt signaling pathway

Definition

Target type: biologicalprocess

Any process that decreases 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:tb]

Negative regulation of canonical Wnt signaling pathway involves a complex interplay of molecular mechanisms that dampen the activity of the Wnt signaling cascade, ultimately preventing excessive or inappropriate activation of target genes. The canonical Wnt pathway is essential for embryonic development, tissue homeostasis, and regeneration, but its dysregulation can contribute to diseases like cancer. Here's a detailed breakdown of the key steps involved in its negative regulation:

**1. Wnt Ligand Absence:** In the absence of Wnt ligands, the signaling pathway is inactive. In this state, the cytoplasmic protein β-catenin is targeted for degradation.

**2. Formation of the Destruction Complex:** A multi-protein complex forms in the cytoplasm, consisting of:
* **Axin:** A scaffold protein that brings together other components of the complex.
* **APC (Adenomatous Polyposis Coli):** A tumor suppressor protein that interacts with β-catenin, promoting its degradation.
* **GSK-3β (Glycogen Synthase Kinase 3 beta):** A kinase that phosphorylates β-catenin, marking it for degradation.
* **CK1 (Casein Kinase 1):** Another kinase that phosphorylates β-catenin, priming it for GSK-3β phosphorylation.

**3. β-catenin Degradation:** The destruction complex phosphorylates β-catenin, targeting it for ubiquitination by the E3 ubiquitin ligase complex. This marks β-catenin for degradation by the proteasome, preventing its accumulation in the cytoplasm.

**4. Inhibition of TCF/LEF Transcription Factors:** In the absence of active Wnt signaling, β-catenin is not present in the nucleus. This allows transcriptional repressor proteins, like Groucho, to bind to TCF/LEF transcription factors, preventing the activation of Wnt target genes.

**5. Wnt Ligand Binding:** When Wnt ligands bind to their cognate receptors (Frizzled and LRP5/6), a signaling cascade is initiated that leads to the activation of the canonical Wnt pathway.

**6. Disassembly of the Destruction Complex:** The binding of Wnt ligands disrupts the destruction complex. This occurs by:
* **Inhibition of GSK-3β:** Wnt signaling activates Dishevelled (Dsh), which inhibits the kinase activity of GSK-3β, preventing it from phosphorylating β-catenin.
* **Axin Sequestration:** Dsh also sequesters Axin, preventing it from assembling the destruction complex.

**7. β-catenin Stabilization:** The inhibition of GSK-3β and Axin sequestration lead to the stabilization of β-catenin. It escapes degradation and accumulates in the cytoplasm.

**8. β-catenin Nuclear Translocation:** Stabilized β-catenin translocates to the nucleus, where it interacts with TCF/LEF transcription factors.

**9. Activation of Wnt Target Genes:** The complex of β-catenin and TCF/LEF displaces the repressor proteins and activates the transcription of Wnt target genes, which regulate cell proliferation, differentiation, and other cellular processes.

**10. Negative Feedback Mechanisms:** The canonical Wnt pathway also has various negative feedback mechanisms that control its activity. For example, Wnt target genes can encode proteins that inhibit Wnt signaling, ensuring proper regulation of the pathway.

**11. Inhibitors of Wnt Signaling:** Several molecules can negatively regulate the Wnt pathway, including:
* **SFRP (Secreted Frizzled-related protein):** These proteins act as antagonists by binding to Wnt ligands, preventing their interaction with Frizzled receptors.
* **DKK (Dickkopf):** These proteins bind to LRP5/6, blocking their interaction with Wnt ligands and inhibiting pathway activation.
* **Wnt Inhibitors (WIF):** These proteins bind to Wnt ligands and prevent them from binding to their receptors.

**12. Degradation of β-catenin:** Even in the presence of Wnt signaling, a certain level of β-catenin degradation is maintained to prevent excessive signaling. This is achieved through the continued activity of GSK-3β and the ubiquitination machinery.

In summary, the negative regulation of the canonical Wnt signaling pathway involves a delicate balance of protein interactions and molecular mechanisms that fine-tune the pathway's activity, ensuring its proper functioning in development, tissue homeostasis, and disease prevention.'
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Proteins (33)

Compounds (613)