Wnt β-Catenin pathway

Wnt Proteins Bind to Frizzled Receptors and Inhibit the Degradation of β-Catenin They were discovered independently in flies and in mice: in Drosophila, the Wingless (Wg) gene originally came to light because of its role as a morphogen in wing development, while in mice, the Int1 gene was found because it promoted the development of breast tumors when activated by the integration of a virus next to it. Both of these genes encode Wnt proteins.There are 19 Wnts in humans, each having distinct, but often overlapping, functions.
 Wnts can activate at least two types of intracellular signaling pathway

1. Wnt/β-catenin pathway (also known as the canonical Wnt pathway), which is centered on the latent transcription regulator β-catenin.

2. Planar polarity pathway, coordinates the polarization of cells in the plane of a developing epithelium and depends on Rho family GTPases. Both of these pathways begin with the binding of Wnts to Frizzled.

The Wnt/β-catenin signaling pathway-

 (A) In the absence of a Wnt signal-

 β-catenin that is not bound to cell–cell adherens junctions interacts with a degradation complex containing APC, axin, GSK3, and CK1. In this complex, β-catenin is phosphorylated by CK1 and then by GSK3, triggering its ubiquitylation and degradation in proteasomes.

In the absence of Wnt signaling, Wnt-responsive genes are kept silent by an inhibitory complex of transcription regulatory proteins of the LEF1/TCF family bound to a co-repressor protein of the Groucho family . In response to a Wnt signal, β-catenin enters the nucleus and binds to the LEF1/TCF proteins, displacing Groucho. The β-catenin now functions as a coactivator, inducing the transcription of the Wnt target genes.Thus, Wnt/β-catenin signaling triggers a switch from transcriptional repression to transcriptional activation. Among the genes activated by β-catenin is Myc, which encodes a protein (Myc) that is an important regulator of cell growth and proliferation .

 (B) In the presence of wnt signal-

 Wnt proteins regulate β-catenin proteolysis by binding to both a Frizzled protein and a co-receptor that is related to the low-density lipoprotein (LDL) receptor  and is therefore called an LDL-receptor-related protein (LRP).  The activated receptor complex recruits the Dishevelled scaffold and the cytosolic tail of LRP is phosphorylated by  a protein kinase called casein kinase 1 (CK1) phosphorylates the β-catenin on a serine. For further phosphorylation by another protein kinase called glycogen synthase kinase 3 (GSK3); this final phosphorylation marks the protein for ubiquitylation and rapid degradation in proteasomes.

Two scaffold proteins called axin and Adenomatous polyposis coli (APC) hold the protein complex together .APC gets its name from the finding that the gene encoding it is often mutated in a type of benign tumor (adenoma) of the colon; the tumor projects into the lumen as a polyp and can eventually become malignant. (This APC should not be confused with the anaphase-promoting complex, or APC/C, that plays a central part in selective protein degradation during the cell cycle.

Axin binds to the phosphorylated LRP and is inactivated and/or degraded, resulting in disassembly of the degradation complex. The phosphorylation of β-catenin is thereby prevented, and unphosphorylated β-catenin accumulates and translocates to the nucleus, where it binds to LEF1/ TCF, displaces the co-repressor Groucho, and acts as a coactivator to stimulate the transcription of Wnt target genes. The scaffold protein Dishevelled is required for the signaling pathway to operate; it binds to Frizzled and becomes phosphorylated .

NOTE -The Wnt/β-catenin pathway acts by regulating the proteolysis of the multifunctional protein β-catenin (or Armadillo in flies).

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