YAP/TAZ as mediators of Wnt signaling

Constitutive activation of the Wnt pathway is a main oncogenic input for several tissues. Wnts are secreted cytokines that interact with membrane receptors, Frizzled and LRP5/6, leading to the inactivation of a cytoplasmic protein complex, named the b-catenin destruction complex. Within this complex, two central scaffold proteins, Axin1/2 and adenomatous polyposis coli (APC), recruit the kinase glycogen synthase kinase-3 (GSK3) to phosphorylate b-catenin promoting its degradation.

We recently found that, in absence of Wnt stimulation, cytoplasmic YAP/TAZ contribute to the function of the destruction complex (Azzolin et al., 2014) (see Figure). YAP/TAZ bind directly Axin, APC and b-catenin, causing their sequestration in the complex, and also causing TAZ to interact with b-TrCP, leading to its degradation (Azzolin et al., 2014; Azzolin et al., 2012). Therefore, Wnt stimulation, depletion of Axin1/2 or of APC release YAP/TAZ from such cytoplasmic sites and promote YAP/TAZ nuclear accumulation and target genes transcription (Azzolin et al., 2014; Azzolin et al., 2012; Byun et al., 2014). YAP/TAZ are upregulated and nuclear after APC loss in the intestine (Azzolin et al., 2014; Cai et al., 2015; Camargo et al., 2007; Gregorieff et al., 2015). Functionally, YAP/TAZ are required downstream to APC mutations for uncontrolled proliferation of the intestinal epithelium and intestinal tumorigenesis (Azzolin et al., 2014; Cai et al., 2015; Gregorieff et al., 2015). In CRC cells bearing inactivating APC mutations, b-catenin and TAZ cooperate to promote cell growth (Azzolin et al., 2012).

Nuclear localization of YAP/TAZ is by itself an event that depletes the destruction complex favoring b-catenin nuclear localization; for example nuclear translocation of YAP/TAZ induced by strong mechanical stimuli - such as those produced by inflammation, fibrosis, or stretching epithelial monolayers - has been recently shown to be sufficient to be followed by b-catenin activation even without overt presence of Wnt ligands (Nowell et al., 2016). Thus, the mechanical control of YAP/TAZ can feedback into the same pathways that control tissue patterning, providing a mean for the cell's structural features to attain a high-order control over growth factor signaling.

Click here for protocols on the monitoring of the effects of Wnt on the transcriptional activity of YAP/TAZ.


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