The Wnt/β-catenin pathway acts by regulating the proteolysis of the multi-functional protein β-catenin (or Armadillo in flies). A portion of the cell’s β-catenin is located at cell–cell junctions and thereby contributes to the control of cell– cell adhesion (discussed in Chapter 19), while the remaining β-catenin is rapidly degraded in the cytoplasm. Degradation depends on a large protein degradation complex, which binds β-catenin and keeps it out of the nucleus while promoting its degradation. The complex contains at least four other proteins: a protein kinase called casein kinase 1 (CK1) phosphorylates the β-catenin on a serine, priming it 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 (Figure 15–60A). 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—see Figure 17–15A.)
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 (discussed in Chapter 13) and is therefore called an LDL-receptor-related protein (LRP). In a poorly understood process, the activated receptor complex recruits the Dishevelled scaffold and promotes the phosphorylation of the LRP receptor by the two protein kinases, GSK3 and CK1. Axin is brought to the receptor complex and inactivated, thereby disrupting the β-catenin degradation complex in the cytoplasm. In this way, the phosphorylation and degradation of β-catenin are prevented, enabling unphosphorylated β-catenin to accumulate and translocate to the nucleus, where it alters the pattern of gene transcription (Figure 15–60B).
Figure 15–60 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 (not shown) 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. Wnt-responsive genes are kept inactive by the Groucho co-repressor protein bound to the transcription regulator LEF1/TCF. (B) Wnt binding to Frizzled and LRP clusters the two co-receptors together, and the cytosolic tail of LRP is phosphorylated by GSK3 and then by CK1. 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 (not shown), but its precise role is unknown.