Interaction of Nuclear Receptors with the Wnt/β-Catenin/Tcf Signaling Axis: Wnt You Like to Know?

Abstract

The cross-regulation of Wnt/beta-catenin/Tcf ligands, kinases, and transcription factors with members of the nuclear receptor (NR) family has emerged as a clinically and developmentally important area of endocrine cell biology. Interactions between these signaling pathways result in a diverse array of cellular effects including altered cellular adhesion, tissue morphogenesis, and oncogenesis. Analyses of NR interactions with canonical Wnt signaling reveal two broad themes: Wnt/beta-catenin modulation of NRs (theme I), and ligand-dependent NR inhibition of the Wnt/beta-catenin/Tcf cascade (theme II). Beta-catenin, a promiscuous Wnt signaling member, has been studied intensively in relation to the androgen receptor (AR). Beta-catenin acts as a coactivator of AR transcription and is also involved in co-trafficking, increasing cell proliferation, and prostate pathogenesis. T cell factor, a transcriptional mediator of beta-catenin and AR, engages in a dynamic reciprocity of nuclear beta-catenin, p300/CREB binding protein, and transcriptional initiation factor 2/GC receptor-interaction protein, thereby facilitating hormone-dependent coactivation and transrepression. Beta-catenin responds in an equally dynamic manner with other NRs, including the retinoic acid (RA) receptor (RAR), vitamin D receptor (VDR), glucocorticoid receptor (GR), progesterone receptor, thyroid receptor (TR), estrogen receptor (ER), and peroxisome proliferator-activated receptor (PPAR). The NR ligands, vitamin D(3), trans/cis RA, glucocorticoids, and thiazolidines, induce dramatic changes in the physiology of cells harboring high Wnt/beta-catenin/Tcf activity. Wnt signaling regulates, directly or indirectly, developmental processes such as ductal branching and adipogenesis, two processes dependent on NR function. Beta-catenin has been intensively studied in colorectal cancer; however, it is now evident that beta-catenin may be important in cancers of the breast, prostate, and thyroid. This review will focus on the cross-regulation of AR and Wnt/beta-catenin/Tcf but will also consider the dynamic manner in which RAR/RXR, GR, TR, VDR, ER, and PPAR modulate canonical Wnt signaling. Although many commonalities exist by which NRs interact with the Wnt/beta-catenin signaling pathway, striking cell line and tissue-specific differences require deciphering and application to endocrine pathology.

9-cis-Retinoic Acid (9cRA), a Retinoid X Receptor (RXR) Ligand, Exerts Immunosuppressive Effects on Dendritic Cells by RXR-Dependent Activation: Inhibition of Peroxisome Proliferator-Activated Receptor γ Blocks Some of the 9cRA Activities, and Precludes Them to Mature Phenotype Development

“…These facts are in agreement with a widespread point of view that there is a close relation among all these receptors, suggesting a complex and tight regulation dependent on secondary messengers and cofactors. This regulation has already been described in macrophages and Wnt signaling in other cell types (61,62) but, to our knowledge, not until now in DCs. In this sense, there would be a nuclear receptor modulation of the DC response depending on the external signaling or the extracellular medium composition, together with an intrinsic stage of the cells.…”

A direct protein-protein interaction is involved in the suppression of β-catenin transcription by retinoid X receptor α in colorectal cancer cells

“…15 It has been reported that RAR interacts with β-catenin and inhibits β-catenin-mediated gene transcription. [16][17][18] But, whether there is an interaction and what is the functional regulation between RXRα and β-catenin are not clear. Using mammalian two-hybridization system in vivo and immunoprecipitation in vitro in this study, we found that RXRα directly interacted with β-catenin, and that RXRα directly inhibited β-catenin transcriptional activity and protein expression in colorectal cancer cell lines.…”

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

“…Canonical Wnt signaling converges with various hormone-signaling pathways through interaction with corresponding nuclear receptors. This crosstalk has been shown to play an important role in the regulation of many vital biological processes, including cell proliferation and carcinogenesis (Moon et al, 2004;Mulholland et al, 2005 and references therein).…”