negative regulation of Wnt-Frizzled-LRP5/6 complex assembly

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of Wnt-Frizzled-LRP5/6 complex assembly. [GO_REF:0000058, GOC:bf, GOC:PARL, GOC:TermGenie, PMID:11433302]

Negative regulation of Wnt-Frizzled-LRP5/6 complex assembly is a crucial biological process that controls the activity of the Wnt signaling pathway. This pathway is essential for a wide range of developmental and physiological processes, including cell proliferation, differentiation, and tissue homeostasis. The Wnt-Frizzled-LRP5/6 complex is a transmembrane receptor complex that initiates the Wnt signaling pathway. It consists of three key components: Wnt ligands, Frizzled receptors, and LRP5/6 co-receptors. Wnt ligands are secreted proteins that bind to Frizzled receptors, which are seven-transmembrane proteins. This binding event recruits LRP5/6 co-receptors, which are single-pass transmembrane proteins, to the complex. The assembly of this complex triggers a cascade of intracellular signaling events that ultimately lead to the activation of downstream target genes. Negative regulation of Wnt-Frizzled-LRP5/6 complex assembly ensures that Wnt signaling is tightly controlled and only activated when appropriate. Several mechanisms contribute to this negative regulation:

1. **Wnt Antagonists**: Several secreted proteins act as Wnt antagonists, preventing Wnt ligands from binding to Frizzled receptors. These antagonists include Dickkopf (Dkk) proteins, sclerostin (SOST), and Wnt inhibitory factor 1 (WIF1).

2. **Frizzled Degradation**: Frizzled receptors can be internalized and degraded, reducing the availability of receptors for Wnt binding. This process is often mediated by the ubiquitin-proteasome system.

3. **LRP5/6 Phosphorylation**: LRP5/6 co-receptors can be phosphorylated at specific residues, which can inhibit their ability to bind to Wnt ligands. This phosphorylation is often carried out by kinases like CK1 and GSK3β.

4. **Scaffolding Proteins**: Some scaffolding proteins, such as Axin and Apc, can sequester components of the Wnt-Frizzled-LRP5/6 complex, preventing them from assembling.

5. **Endocytosis**: The Wnt-Frizzled-LRP5/6 complex itself can be internalized and degraded through endocytosis. This process can be regulated by various factors, including the availability of clathrin and adaptor proteins.

In summary, negative regulation of Wnt-Frizzled-LRP5/6 complex assembly is a complex process involving multiple mechanisms that act at different levels. This fine-tuning of Wnt signaling is essential for maintaining normal development and preventing disease. Dysregulation of Wnt signaling has been implicated in various diseases, including cancer, bone diseases, and neurological disorders.'
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Proteins (1)

Compounds (1)