Role and regulation of β-catenin signaling during physiological liver growth

Abstract

Wnt/β-catenin signaling plays key roles not only during development but also in adult tissue homeostasis. This is also evident in liver biology where many temporal roles of β-catenin have been identified during hepatic development, where, in hepatic progenitors or hepatoblasts, it is a key determinant of proliferation and eventually differentiation to mature hepatocytes, while also playing an important role in bile duct homeostasis. β-Catenin signaling cascade is mostly quiescent in hepatocytes in an adult liver except in the centrizonal region of a hepatic lobule. This small rim of hepatocytes around the central vein show constitutive β-catenin activation that in turn regulates expression of genes whose products play an important role in ammonia and xenobiotic metabolism. Intriguingly, β-catenin can also undergo activation in hepatocytes after acute liver loss secondary to surgical or toxicant insult. Such activation of this progrowth protein is observed as nuclear translocation of β-catenin and formation of its complex with the T-cell factor (TCF) family of transcription factors. Expression of cyclin-D1, a key inducer of transition from the G1 to S phase of cell cycle, is regulated by β-catenin-TCF complex. Thus, β-catenin activation is absolutely critical in the normal regeneration process of the liver as shown by studies in several models across various species. In the current review, the temporal role and regulation of β-catenin in liver development, metabolic zonation in a basal adult liver, and during the liver regeneration process will be discussed. In addition, the probability of therapeutically regulating β-catenin activity as a possible future treatment strategy for liver insufficiency will also be discussed.

Figure 1

Various mechanisms leading to β-catenin activation in a cell. While Wnt signaling (1) is the chief upstream effector of β-catenin, which allows its stabilization by inhibiting its degradation complex, E-cadherin–β-catenin complex at adherens junctions (2) is susceptible to various receptor tyrosine kinases that allow tyrosine phosphorylation-dependent β-catenin activation. Protein kinase A (3) through G protein-coupled receptor activation has been shown to directly phosphorylate β-catenin at serine 552 and serine 675 and induce its activation. Last, growth factors such as TGF-β and FGFs have been shown to activate β-catenin (4) through less well understood mechanisms that may or may not involve protein kinase A (LRP5/6, LDL-related protein 5 or 6; CK1ε, casein kinase 1 ε; GSK3β, glycogen synthase kinase 3β; APC, adenomatous polyposis coli gene product; GF, growth factors; HGF, hepatocyte growth factor; EGF, epidermal growth factor; PKA, protein kinase A; GPCR-G protein-coupled receptor; TGF-β, transforming growth factor-β; FGF, fibroblast growth factor; TCF, T-cell factor; LEF, lymphoid enhancement factor).

Figure 2

A schematic depicting hypothesis of how truncated β-catenin may have distinct functions than full-length form during liver development. We speculate that conformational change in β-catenin due to calpain-mediated cleavage that yields truncated β-catenin (T) may be permissive to its interactions with distinct transcription factor (TF2) compared to full-length β-catenin (FL) that interacts normally with TF1. This switch may correspond to disparate functions of the two forms during normal liver development (see text for more details).

Figure 3

β-Catenin immunohistochemistry in normal adult mouse liver. Predominantly, β-catenin is observed staining hepatocyte membrane only in both the midzonal (purple box) and periportal regions of a hepatic lobule, where it interacts with E-cadherin and constitutes the adherens junctions. Around the central vein (CV), β-catenin, in addition to being membranous, is also cytoplasmic and nuclear (blue box) where it acts as a downstream effector of the Wnt signaling pathway and regulates pericentral target gene expression.

Figure 4

A schematic representing cellular basis of Wnt/β-catenin activation during liver regeneration process. Nonparenchymal cells are the source of several key Wnt proteins that, in a paracrine manner, stimulate β-catenin activity in neighboring hepatocytes, which in turn induces cyclin-D1 expression to facilitate G₁- to S-phase cell cycle transition that is essential for hepatocyte proliferation during liver regeneration process (TCF, T-cell factor; CBP, CREB-binding protein).