β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis

Abstract

β-catenin (encoded by CTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signal transducer in the WNT signaling pathway; alterations in its activity have been associated with the development of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signaling pathways also can converge at β-catenin. β-catenin also interacts with transcription factors such as T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α to regulate the expression of target genes. We discuss the role of β-catenin in metabolic zonation of the adult liver. β-catenin also regulates the expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in its activity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in β-catenin signaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatic tumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations in CTNNB1 that result in constitutive activation of β-catenin, so this molecule could be a therapeutic target. We discuss how alterations in β-catenin activity contribute to liver disease and how these might be used in diagnosis and prognosis, as well as in the development of therapeutics.

Keywords: E-Cadherin; HCC; Liver Fibrosis; Liver Tumors; NASH; WNT; β-Catenin.

Figure 1

WNT Signaling via β-catenin. (A) In the absence of WNT or in the presence of WNT inhibitors, β-catenin is phosphorylated at specific serine and threonine residues in exon 3 by kinases in the degradation complex, leading to recognition by β-transducin repeat-containing protein for destruction. Mutations affecting these residues can lead to stabilization of the β-catenin protein. (B) WNT protein is palmitoylated and glycosylated by porcupine (Porcup) in the endoplasmic reticulum and transported by wntless (WLS) protein from the Golgi apparatus to the membrane for secretion. Secreted WNT binds to its receptor (FZ) and co-receptors LRP5 or LRP6. The signal is transduced through disheveled to inactivate the β-catenin degradation complex, leading to nuclear translocation of β-catenin. In the nucleus, β-catenin interacts with LEF/TCF transcription factors to regulate the expression of target genes. (C) WNT5A either can activate or inhibit β-catenin signaling, depending on the type of FZD expressed by a cell. WNT5A can activate β-catenin signaling in the presence of frizzled-4 (FZD4), although it inhibited β-catenin in the presence of FZD2 or an alternate WNT receptor called the receptor tyrosine kinase-like orphan receptor 2. β-cat, β-catenin; CK, casein kinase; Dsh, disheveled; P, phosphorylation; WIF, WNT inhibitory factor.

Figure 2

β-catenin structure and role in adherens junctions. (A) Specific amino acids in β-catenin regulate its stability, activity, and interactions with other proteins. (B) In a normal liver, β-catenin acts as a bridge between the intracytoplasmic tail of E-cadherin and the actin cytoskeleton to regulate cell adhesion. Molecules such as HGF, EGF, FER kinase, and SRC can affect this complex negatively through tyrosine phosphorylation of β-catenin at specific residues. The end result of dissociation of the complex in some cases can result in nuclear translocation and activation of β-catenin. Left: in the absence of β-catenin, γ-catenin is able to maintain AJs by binding to E-cadherin and actin cytoskeleton. γ-Catenin did not compensate for nuclear β-catenin function. EGF, epidermal growth factor; JAM-A, junctional adhesion molecule-A; jxns, junctions.

Figure 3

Interactions among β-catenin, HNF4α, and TCF4 in periportal and pericentral hepatocytes. (Left panel) β-catenin binds to TCF4 and this complex binds to WNT response elements in promoters of target genes in pericentral hepatocytes. Here, TCF can bind to the HNF4α response elements, making it unavailable for HNF4α to bind and transactivate its target genes. Furthermore, β-catenin can bind HNF4α to prevent its binding to gene promoters. β-catenin signaling via TCF4 therefore is activated and HNF4α transactivation is inactivated in these cells. (Right panel) In periportal hepatocytes, HNF4α binds to HNF4α response elements in promoters of target genes to induce their expression while also occupying WNT response elements, preventing TCF binding. Furthermore, HNF4α can bind β-catenin and TCF to keep them engaged and prevent binding to target gene promoters. HNF4α signaling therefore is activated and β-catenin signaling via TCF4 is inactivated in these cells. β-cat, β-catenin.

Figure 4

WNT signaling to β-catenin during adipogenesis and activation of hepatic stellate cells. Inhibition of WNT signaling to β-catenin is required for differentiation of pre-adipocytes into adipocytes, regulating expression of genes that control adipogenesis such as PPARγ and CCAAT enhancer binding protein-α (CEBPα). HSC differentiation into active myofibroblasts is analogous to de-differentiation of adipocytes to preadipocytes (losing adipogenic properties). WNT activation of β-catenin promotes this process by negatively regulating the expression of PPARα and CEBPα. WNT signaling via β-catenin therefore might be inhibited to treat patients with fibrosis: it would activate the expression of genes involved in adipogenesis-induced quiescence of activated stellate cells.