A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-catenin signalling

Abstract

The Hippo signalling pathway has emerged as a key regulator of organ size, tissue homeostasis, and patterning. Recent studies have shown that two effectors in this pathway, YAP/TAZ, modulate Wnt/b-catenin signalling through their interaction with b-catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/b-catenin signalling. We show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of b-catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to b-catenin, thereby suppressing Wnt-target gene expression, and that the Hippo pathway-stimulated phosphorylation of YAP, which induces cytoplasmic translocation of YAP, is required for the YAP-mediated inhibition of Wnt/b-catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of b-catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of b-catenin by directly binding to it in the cytoplasm. These results provide a novel mechanism, in which Hippo signalling antagonizes Wnt signalling by regulating nuclear translocation of b-catenin.

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

“…On the basis of previous observations that both TGF-b and Wnt pathways are regulated by Hippo signaling (16)(17)(18), we determined whether they would be also inhibited by C19. The results indicate that this was the case (Fig.…”

“…In fact, evidence from expression studies in patient tumor specimens, transgenic animals, and in vitro experiments, all confirmed inappropriate activation of the canonical Wnt signaling as a major feature in human neoplasia (15). Interestingly, both TGF-b and Wnt signaling were recently found to be regulated by a developmental pathway called Hippo (16)(17)(18). The latter was initially described in drosophila for its ability to control organ size (19).…”

“…Its role in EMT was demonstrated by studies in which nonphosphorylated (active) Hippo transducers YAP, TAZ, and TEAD were found to act either together, in conjunction with b-catenin/TCF, or with Smads (20,21) to induce genes that regulate cell morphology, migration, and cancer metastasis. Phosphorylation (inactivation) of the Hippo transducers is carried out by upstream kinases (Mst/Lats) resulting in their cytoplasmic retention and either proteasomal degradation (22) by the GSK3-b-associated degradation complex or sequestration of b-catenin and Smads thereby inhibiting the trans-activation of these transcription factors (16)(17)(18).…”

Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis

“…These results suggest that SFKs negatively regulate Wnt-␤-catenin signaling. Given that YAP is thought to inhibit the Wnt-␤-catenin signaling pathway (48)(49)(50), SFKs likely target this pathway through upregulation of YAP activity in crypt IECs. We also found that IEC-specific ablation of Csk increased the number of goblet cells in the ileum as well as in intestinal organoids and that expression of the Notch target genes Olfm4 and Hes1 (9, 51) was downregulated in crypts of Csk CKO mice ( Fig.…”

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

“…A particularly intriguing intersection is the pathway involving the YAP/TAZ transcriptional regulators, which govern proliferation in a variety of cells and tissues. YAP/ TAZ can be regulated by mechanosensing, a feature that can block its inhibitory kinase, Hippo, and enable YAP/ TAZ to translocate into the nucleus and function as transcriptional cofactors for the TEAD family of DNAbinding proteins (Varelas et al 2010;Heallen et al 2011;Azzolin et al 2012;Imajo et al 2012;Aragona et al 2013). Hippo signaling can also regulate b-catenin, and, reciprocally, YAP/TAZ can inhibit Wnt/b-catenin signaling (Varelas et al 2010;Heallen et al 2011;Imajo et al 2012).…”