Wnt, RSPO and Hippo Signalling in the Intestine and Intestinal Stem Cells.

Vitezslav Kriz,Vladimir Korinek

doi:10.3390/genes9010020

Abstract

In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In the ON state, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the Hippo OFF state, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL pool. Wnt ligands can trigger alternative signalling that directly involves some of the Hippo pathway components such as YAP1, TAZ and TEADs. By upregulating Wnt pathway agonists, the alternative Wnt signalling can inhibit the canonical Wnt pathway activity.

Highlights

In this review, we describe the molecular mechanisms and possible crosstalk of the signalling pathways that directly influence intestinal homeostasis and tumorigenesis
YAP1/TAZ are dispensable for intestinal homeostasis; upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation
In agreement with these observations were data showing that the growth of intestinal organoids depends on Wnt agonists R-Spondins (RSPOs) and organoids derived from adenomatous polyposis coli (APC)-deficient intestinal tumours lost this dependency [8,9]

Summary

Introduction

We describe the molecular mechanisms and possible crosstalk of the signalling pathways that directly influence intestinal homeostasis and tumorigenesis. In 1998, these results were complemented by gene targeting in the mouse, showing that upon ablation of the β-catenin interacting partner TCF4, proliferative compartments in the small intestine are not formed [7]. In agreement with these observations were data showing that the growth of intestinal organoids depends on Wnt agonists R-Spondins (RSPOs) and organoids derived from APC-deficient intestinal tumours lost this dependency [8,9]. Koo and colleagues reported that RSPO/LGR signalling potentiates the surface expression of Wnt receptors frizzled (FZD) [10] These findings seemingly completed our perception of the Wnt pathway as the major regulatory mechanism involved in intestinal epithelium renewal and transformation. We summarized some results obtained upon gene inactivation of individual RSPO ligands and LGR receptors in the mouse

Intestinal Epithelium Architecture and Cellular Composition

Wnt Signalling in the Intestine

The Hippo Pathway