β-catenin signaling: a novel mediator of fibrosis and potential therapeutic target

Abstract

Purpose of review: The Wnt/β-catenin signaling pathway plays a critical role in development and adult tissue homeostasis. Recent investigations implicate Wnt/β-catenin signaling in abnormal wound repair and fibrogenesis. The purpose of this review is to highlight recent key studies that support a role for Wnt/β-catenin signaling in fibrosis.

Recent findings: Studies of patients with fibrotic diseases have demonstrated changes in components of the Wnt/β-catenin pathway. In animal models, perturbations in Wnt/β-catenin signaling appear to aggravate or ameliorate markers of injury and fibrosis in a variety of different tissues. Studies also suggest that fibroblasts from different tissue sources may have markedly divergent responses to Wnt/β-catenin signaling. Cross-talk between Wnt/β-catenin and transforming growth factor-β pathways is complex and context-dependent, and may promote fibrogenesis through coregulation of fibrogenic gene targets. High throughput screening has identified several novel chemical inhibitors of Wnt/β-catenin signaling that may be of therapeutic potential.

Summary: Wnt/β-catenin signaling appears important in normal wound healing and its sustained activation is associated with fibrogenesis. The mechanism by which Wnt/β-catenin signaling may modify the response to injury is cell-type and context-dependent. Better understanding of this signaling pathway may provide a promising new therapeutic approach for human fibrotic diseases.

Figure 1. Wnt pathway basics

In the absence of Wnt (left), cytosolic β-catenin is continually phosphorylated by casein kinase 1α (CK1α) and glycogen synthase kinase 3β (GSK-3β) within an Axin1 scaffold complex. This phosphorylation allows β-catenin to be recognized by a specific E3 ligase (βTrCP, not shown), which catalyzes the ubiquitylation and rapid degradation of β-catenin. The adenomatous polyposis coli (APC) tumor suppressor participates in the phosphodestruction of β-catenin by antagonizing β-catenin dephosphorylation by phosphatases. During Wnt activation (right), GSK3β activity is inhibited directly by LDL receptor related protein 5 and 6 (LRP5/6), which allows β-catenin to accumulate, enter the nucleus, interact with LEF/TCF family members and activate target genes. Fibrosis-relevant targets of Wnt/β-catenin signaling remain to be clarified. General targets of Wnt/β-catenin signaling include negative feedback regulators, Axin2, Naked (NKD) and Dickkopf (DKK).

Figure 2. Inhibitors of Wnt/β-catenin and their sites of action

APC, adenomatous polyposis coli; CBP, CREB binding protein; CK1α, casein kinase 1α; GSK-3β, glycogen synthase kinase 3β; iCRT, inhibitor of catenin responsive transcription; TCF, T-cell factor. See text for details.