Nuclear Regulation of Wnt/β-Catenin Signaling: It's a Complex Situation

Abstract

Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. Misregulation of Wnt/β-catenin signaling has been implicated in developmental defects in the embryo and major diseases in the adult. Despite the latter, no drugs that inhibit the Wnt/β-catenin pathway have been approved by the FDA. In this review, we explore the least understood step in the Wnt/β-catenin pathway-nuclear regulation of Wnt target gene transcription. We initially describe our current understanding of the importation of β-catenin into the nucleus. We then focus on the mechanism of action of the major nuclear proteins implicated in driving gene transcription. Finally, we explore the concept of a nuclear Wnt enhanceosome and propose a modified model that describes the necessary components for the transcription of Wnt target genes.

Keywords: BCL9; Pygopus; TCF/LEF; TLE; Wnt/β-catenin signaling; enhanceosome; nuclear regulation.

Figure 1

Model of the Wnt pathway. (a)—ln the absence of Wnt ligand, the β-catenin β destruction complex maintains low cytoplasmic levels of β-catenin. (b)—In the presence of Wnt ligand, the signalosome is assembled and the β-catenin degradation is disrupted. Entry of β-catenin into the nucleus promotes the formation of the enhanceosome to drive the transcription of Wnt target genes. See text for more details.

Figure 2

Cartoon of β-catenin and its nuclear interacting partners.

Figure 3

Proposed modified model of a Wnt enhanceosome with a β-catenin-TCF/LEF core complex and other requisite components that are context dependent. We propose that at least four additional components are required to form a functional enhanceosome: (1) a chromatin remodeling complex (e.g., SET-1, a histone methyltransferase, and CBP/p300, a histone acetyltransferase) that promotes gene transcription; (2) a bridging factor to link enhancer regions to the WRE and which may coordinate context-dependent factors (e.g., the ChILS complex and BCL9); (3) a mediator recruiter (e.g., Pygo and β-catenin); (4) an E3 ubiquitin ligase that promotes Gro/TLE dissociation from TCF/LEF (e.g., XIAP or Hyd/UBR5).