Wnt signalosome assembly

Definition

Target type: biologicalprocess

The aggregation, arrangement and bonding together of a set of components to form a Wnt signalosome. [GO_REF:0000079, GOC:bf, GOC:PARL, GOC:TermGenie, PMID:22899650]

Wnt signalosome assembly is a complex and tightly regulated process that governs the activation of the Wnt signaling pathway, a crucial regulator of embryonic development, tissue homeostasis, and various cellular functions. The Wnt pathway, characterized by its dependence on the secreted Wnt proteins, is a complex network of signaling events that culminate in the modulation of gene expression. The Wnt signalosome, the molecular machinery responsible for relaying the Wnt signal, assembles at the plasma membrane and undergoes intricate rearrangements and protein interactions to activate downstream signaling cascades. Here is a detailed breakdown of the intricate steps involved in Wnt signalosome assembly:

1. **Ligand Binding and Receptor Activation:** The journey begins with the binding of Wnt proteins, a family of secreted glycoproteins, to their cognate receptors, Frizzled (Fz) proteins, on the cell surface. This binding event triggers a conformational change in Fz, initiating the assembly process.

2. **Lrp5/6 Recruitment and Coreceptor Interaction:** Simultaneously, Wnt proteins also bind to Lrp5 or Lrp6, a coreceptor crucial for the stability and activation of the signalosome. This interaction brings Lrp5/6 into close proximity to Fz, facilitating their association.

3. **Dishevelled (Dvl) Recruitment and Activation:** The binding of Wnt to Fz activates a cascade of protein-protein interactions, culminating in the recruitment and activation of Dishevelled (Dvl), a pivotal signaling protein. Dvl acts as a central hub, bridging the initial signaling events at the membrane with downstream signaling cascades.

4. **Axin and GSK3β Interaction:** Axin, a scaffolding protein, plays a critical role in stabilizing the signalosome and regulating its activity. Axin interacts with Lrp5/6, forming a complex that also includes GSK3β, a kinase that typically inhibits Wnt signaling. This interaction tethers GSK3β to the signalosome, positioning it for its role in regulating downstream signaling.

5. **β-catenin Stabilization and Nuclear Translocation:** The assembly of the Wnt signalosome triggers a series of events that culminate in the stabilization of β-catenin, a key transcription factor. In the absence of Wnt signaling, β-catenin is continuously phosphorylated by GSK3β, targeting it for degradation. However, upon Wnt signalosome assembly, Dvl, in conjunction with other signaling proteins, inhibits GSK3β activity, preventing β-catenin phosphorylation. This stabilization allows β-catenin to accumulate in the cytoplasm and eventually translocate to the nucleus.

6. **Transcriptional Regulation and Target Gene Activation:** Once in the nucleus, β-catenin forms a complex with TCF/LEF transcription factors, activating the transcription of Wnt target genes. These genes encode proteins essential for cell growth, proliferation, differentiation, and various developmental processes.

7. **Signalosome Disassembly and Feedback Regulation:** The Wnt signalosome is not a static entity; it undergoes constant assembly and disassembly, ensuring the fine-tuning of Wnt signaling. Multiple mechanisms are involved in signalosome disassembly, including the degradation of components like β-catenin and the removal of Wnt ligands from the cell surface. These processes prevent excessive signaling and maintain cellular homeostasis.

In summary, Wnt signalosome assembly is a tightly regulated process that involves intricate protein-protein interactions and signaling cascades, ultimately leading to the activation of Wnt target genes. This elaborate process underscores the importance of Wnt signaling in regulating critical cellular processes, highlighting its role in development, tissue homeostasis, and disease.'
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Proteins (1)

Compounds (88)