Wnt-β-catenin Signaling

Wnt-β-catenin signaling

β-Catenin is the core protein of the Wnt signaling cascade. When localized to the plasma membrane, β-Catenin acts as a bridge between E-cadherin and cytoskeleton-associated actin to form adherent junctions between cells, when localized to the cytoplasm, β-catenin acts as the molecular effector of Wnt signaling. In the absence of extracellular Wnt ligands, the canonical Wnt-β-catenin pathway is inactive (Wnt-off state). By contrast, in the activated (Wnt-on) state, β-catenin functions as a central effector of the canonical Wnt signaling cascade. Wnt ligands constitute a large family of glycoproteins that are secreted in autocrine and paracrine manners by many cell types under different circumstances. Although Wnt signaling is tightly regulated intracellularly, this pathway is also modulated by extracellular antagonists, inhibitors, Norrin and R-spondins. In addition Wnt signaling can also act independently of β-catenin, through the less understood non-canonical or alternative Wnt pathways.

Liver development

Endoderm patterning. Wnt-β-catenin components, together with fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs), enable the Nodal-mediated initiation of gastrulation in animals. Wnt-regulated Nodal expression is a key event in the specification of the gut endoderm, which after gastrulation acquires a tube-like structure surrounded by the mesoderm.

Liver morphogenesis and expansion. Cells residing within the liver bud can rapidly proliferate, resulting in liver bud expansion. Hepatoblasts produce albumin and α-fetoprotein (AFP), both late-stage indicators of hepatic fate commitment. β-Catenin activation is critical for hepatoblast proliferation and specification.

Hepatoblast differentiation. Several ex vivo and in vivo experiments have revealed the importance of β-catenin in hepatocyte and biliary differentiation. For example, deletion of Apc in mice leads to β-catenin stabilization in hepatoblasts, which seems to enhance biliary differentiation and suppresses hepatocyte fate commitment.

Non-tumour liver diseases

Fibrosis. Liver fibrosis is a pathological condition shared by chronic liver diseases of diverse aetiologies. Hepatic stellate cells (HSCs) are the main profibrogenic cells in the liver. Genetic polymorphisms in key members of Wnt-β-catenin pathway have been associated with inflammation and fibrosis in patients with hepatitis C. Interfering with the Wnt-β-catenin pathway using different strategies can modulate liver fibrosis. Furthermore, several proteins stimulate HSC activation and fibrosis by interacting with Wnt-β-catenin. Notably, the Wnt-β-catenin pathway has also been suggested to ameliorate fibrosis under certain conditions.

Liver steatosis. The Wnt-β-catenin pathway seems to participate in NAFLD (Nonalcoholic fatty liver disease) and NASH(Nonalcoholic steatohepatitis) development and progression. Animal models of cancer-related steatosis show Wnt-β-catenin activation, which enhances the growth of tumour-initiating cells.

Cholestasis. Cholestasis is characterized by a reduced bile flow, which often results in accumulation of toxic cholephilic substances such as bile acids, which can cause liver damage, the Wnt-β-catenin pathway participates in the regulation of bile flow. Primary biliary cholangitis and primary sclerosing cholangitis are two chronic cholestatic liver diseases, the Wnt-β-catenin pathway are upregulated in both primary biliary cholangitis and primary sclerosing cholangitis.

Cystogenesis. Polycystic liver diseases (PLDs) are a heterogeneous group of genetic disorders. The identification of LRP5 mutations in a small subset of patients with ADPLD suggests a link between hepatic cystogenesis and Wnt signaling. Remarkably, these mutations induce defects in LRP5 protein structure that impair the activation of Wnt signaling upon Wnt3a treatment in cystic human cholangiocytes.