YAP/TAZ Incorporation in the β-Catenin Destruction Complex Orchestrates the Wnt Response

Abstract

The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression.

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

“…1). Upon Wnt stimulation, YAP/ TAZ is released from the destruction complex, and this in turn promotes b-catenin's stabilization and activation as well as YAP's nuclear translocation (Azzolin et al 2014). Whether YAP/TAZ and b-catenin transcriptional programs coordinately govern stem cell behavior in homeostasis and wound repair and, if so, how are not yet clear.…”

“…Such differences are likely to profoundly impact the ways in which canonical Wnt signaling is perceived and used by tissue stem cells. In this regard, differences in the mechanical properties of these tissues might be particularly relevant, given that both mechanotransduction and canonical Wnt signaling can activate YAP/TAZ and in turn affect homoeostasis (Azzolin et al 2014). Although our review concentrated primarily on the stem cells of the hair follicle, intestine, and epidermis, it is important to note that many of these general issues are likely to apply to other stem cells, including those of the mammary gland and the hematopoietic and nervous systems, where Wnt/b-catenin signaling has been shown to modulate their function (Holland et al 2013;Ring et al 2014;Van Camp et al 2014).…”

“…While many reports indicated that the Wnt/b-catenin pathway is required for the establishment and self-renewal of ES cells (for example, Sato et al 2004;ten Berge et al 2011), others have found that its activation results in differentiation toward mesoderm and endoderm lineages (Lindsley et al 2006;Bakre et al 2007;Davidson et al 2012). Although some of these seemingly opposing differences can be attributed to differences between human and mouse ES cells, relative differences in levels of Wnt signaling are well known to affect cell fate outcome and could be a contributing factor (for review, see Merrill 2012).…”

“…This complex is composed of the core proteins Axin, CK1a, APC, and GSK3b. Like b-catenin, YAP/TAZ can also associate with this complex and in fact is essential for its recruitment of the b-TrCP E3 ubiquitin ligase, which ubiquinates and targets b-catenin for its degradation (Azzolin et al 2014). Binding ofwith the Wnt/b-catenin pathway via an interaction between c-JUN and TCF4 (Nateri et al 2005).…”

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

“…(2012). 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).…”