Wnt target genes and where to find them

Abstract

Wnt/β-catenin signaling is highly conserved throughout metazoans, is required for numerous essential events in development, and serves as a stem cell niche signal in many contexts. Misregulation of the pathway is linked to several human pathologies, most notably cancer. Wnt stimulation results in stabilization and nuclear import of β-catenin, which then acts as a transcriptional co-activator. Transcription factors of the T-cell family (TCF) are the best-characterized nuclear binding partners of β-catenin and mediators of Wnt gene regulation. This review provides an update on what is known about the transcriptional activation of Wnt target genes, highlighting recent work that modifies the conventional model. Wnt/β-catenin signaling regulates genes in a highly context-dependent manner, and the role of other signaling pathways and TCF co-factors in this process will be discussed. Understanding Wnt gene regulation has served to elucidate many biological roles of the pathway, and we will use examples from stem cell biology, metabolism, and evolution to illustrate some of the rich Wnt biology that has been uncovered.

Keywords: T-cell factor; Wnt; beta-catenin; gene regulation; target location.

Figure 1.. Overview of vertebrate Wnt/β-catenin (Wnt/β-cat) signaling.

Wnt binding to Frizzled (Fzd) and low-density lipoprotein receptor-related protein 5/6 (Lrp5/6) co-receptors promotes the phosphorylation of Lrp5/6’s cytoplasmic tail. These interactions block the ability of the destruction complex to phosphorylate and ubiquitinate β-cat, preventing its degradation by the proteasome. Stabilized β-cat enters the nucleus, where it is recruited to Wnt-regulated enhancers by transcription factors (TFs) of the T-cell factor (TCF) family. R-spondin (Rspo) potentiates Wnt/β-cat signaling by increasing the number of Fzd receptors. Rspo forms a complex with Lgr4/5/6 and zinc and ring finger 3 (Znrf3)/ring finger protein 43 (Rnf43), preventing the latter from ubiquitinating Fzd receptors. APC, adenomatous polyposis coli; CKI, casein kinase I; GSK3, glycogen synthase kinase 3; β-TrCP, β-transducin repeat-containing E3 ubiquitin protein ligase.