Cross-regulation of signaling pathways: an example of nuclear hormone receptors and the canonical Wnt pathway

Abstract

Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

Figure 1. Wnt and NHR Crosstalk in Stem Cell Differentiation

(A) Differentiation of mesenchymal stem cells is modulated by the key regulators PPARγ (adipogenesis) and Wnt (osteogenesis). A host of NHRs play a role in modulating the activity of these two key regulators. Glucocorticoid inhibits Wnt signaling by increasing the expression of Wnt antagonists DKK and sFRP (extracellular) and Axin (intracellular) and also by decreasing the expression of Wnts. PPARγ is also able to inhibit Wnt signaling by inducing the degradation of β-catenin under specific conditions. VDR can modulate differentiation by inhibiting DKK and sFRP, which pushes the cells towards osteoblast differentiation. Wnt, itself, can propagate osteogenesis by inhibiting PPARγ activity via the expression of Cyclin D1 and c-myc, which bind to PPARγ and inhibit its activity. β-catenin also increases the expression COUP-TFII, which represses PPARγ transcription. (B) Embryonic stem cells differentiate down a neuronal path under the influence of retinoic acid (RA), which is known to inhibit the Wnt pathway. RA activity also induces body axis extension in the developing embryo. This Wnt inhibition is, in part, effected by an RA-mediated increase in Wnt antagonists, Fzd and DKK. Wnts are responsible for caudal development in the mouse and dorsal development in the frog. A potential negative-feedback loop occurs during Wnt-mediated inhibition of CYP26, an enzyme that metabolizes RA. (C) Keratinocyte stem cells differentiate into sebocytes, follicle keratinocytes or epidermal keratinocytes, which comprise the interfollicular epidermis. VDR and β-catenin cooperate to induce differentiation into follicle keratinocytes, however, perturbation of β-catenin or VDR (independently of each other) leads to cysts that contain epidermal keratinocytes and sebocytes.

Figure 2. β-Catenin-Mediated Crosstalk with NHRs in the Nucleus

Degrees of transcriptional activation/repression are indicated on a scale with + being activation, ++ being increased activation, +++ being synergistic activation, and − being inhibition. (A) TCF and NHR compete for binding to β-Catenin. In the presence of agonist, activated NHR usurps β-catenin from TCF:β-catenin complexes. This synergistically activates NHR-responsive genes. At the same time, TCF, in the absence of β-catenin, is able to repress its gene promoters. (B) TCF and NHR compete for co-activators other than β-catenin. Activated NHR recruits p300 away from TCF:β-Catenin complexes, decreasing or inhibiting Wnt responsive genes, while enhancing NHR-regulated genes. (C) β-catenin is recruited to adherens junctions. E-cadherin is a transcriptional target of activated NHRs. Once it is translated, it can recruit cytoplasmic β-catenin to the membrane, preventing it from co-activating both Wnt responsive genes and NHR responsive genes. (D) NHRs bind TCF and β-catenin. NHRs can bind to TCF/LEF family members and repress genes by recruiting classical NHR co-repressors such as NCoR/SMRT and classical TCF co-repressors such as TLE. β-catenin may, or may not be found in the same complex with TCF/NHR/co-repressors. The transcriptional outcome of β-catenin binding the same complex is still unclear.