Role of TAZ as Mediator of Wnt Signaling

Abstract

Wnt growth factors are fundamental regulators of cell fate, but how the Wnt signal is translated into biological responses is incompletely understood. Here, we report that TAZ, a biologically potent transcriptional coactivator, serves as a downstream element of the Wnt/β-catenin cascade. This function of TAZ is independent from its well-established role as mediator of Hippo signaling. In the absence of Wnt activity, the components of the β-catenin destruction complex--APC, Axin, and GSK3--are also required to keep TAZ at low levels. TAZ degradation depends on phosphorylated β-catenin that bridges TAZ to its ubiquitin ligase β-TrCP. Upon Wnt signaling, escape of β-catenin from the destruction complex impairs TAZ degradation and leads to concomitant accumulation of β-catenin and TAZ. At the genome-wide level, a substantial portion of Wnt transcriptional responses is mediated by TAZ. TAZ activation is a general feature of Wnt signaling and is functionally relevant to mediate Wnt biological effects.

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

“…We evaluated gene signatures comprising MAPK or β-catenin target genes, as well as signature genes enriched in stem cells or proliferative committed TA cells of the intestinal epithelium. [29][30][31][32] As expected, we found that a signature of MAPK target genes was strongly induced by BRAF V600K in ISCs when compared with luciferase-expressing control ISCs. However, signatures of β-catenin target genes were not significantly changed.…”

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

“…At the heart of the canonical Wnt signaling pathway is the silencing of glycogen synthase kinase 3b (GSK3b), which, if active, phosphorylates the N terminus of any cytoplasmic b-catenin not used in cell-cell adhesion (Hart et al 1999;Liu et al 1999a). GSK3b forms a complex with Axin, a priming kinase for b-catenin called casein kinase 1a (CK1a), adenomatous polyposis coli (APC), and YAP/TAZ Lee et al 2003;Azzolin et al 2012). Also present in this so-called destructive complex is the b-transducin repeat-containing protein (b-TrCP) E3 ligase, which ubiquitinates phosphorylated b-catenin and targets it for proteasomal degradation ( Fig.…”

“…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).…”

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

“…Recently, Yes‐associated protein 1 (YAP1) and related transcriptional coactivator TAZ [alternative name for WW domain‐containing transcription regulator 1 (WWTR1)] were discovered as critical components of the β‐catenin destruction complex (Azzolin et al ., 2014). Wnt signaling stabilizes TAZ and promotes TAZ‐dependent transcriptional activation of genes regulated by the TEA domain/Transcription Enhancer Factor (TEAD) family of transcription factors, the main binding partners of both TAZ and YAP1 (Azzolin et al ., 2012). Moreover, β‐catenin and Yes‐associated protein (YAP) act as coactivators of the T‐BOX 5 (TBX5) nuclear factor (Rosenbluh et al ., 2012).…”