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  • Interestingly studies from Sahai and

    2022-05-17

    Interestingly, studies from Sahai and colleagues in cancer-associated fibroblasts have revealed that YAP is required for the acquirement of a stiff ECM in the tumor microenvironment (Calvo et al., 2013). Subsequently, this stiffening of the matrix can activate YAP, thus creating a feed-forward loop. Importantly, inhibition of ROCK was sufficient to break this loop (Calvo et al., 2011, Calvo et al., 2013).
    YAP in relation to Epac1, Rac1 and β-catenin In the previous section, we have discussed the role of the Hippo pathway effector YAP in mechanotransduction. In recent years, knowledge on the complexity of YAP regulation has expanded with the identification that YAP is involved in other pathways that play important roles in cancer as well, especially GPCRs and the β-catenin pathway. YAP can be sequestered in the cytoplasm as part of the APC/Axin/GSK3β/CK1 destruction complex that normally controls levels of free cytosolic β-catenin. Upon Wnt ligand-receptor engagement, cytoplasmic sequestration of YAP by this complex is blocked, leading to nuclear translocation of YAP as well as β-catenin stabilization (Azzolin et al., 2014, Imajo et al., 2012). Inside the nucleus, YAP can interact with β-catenin, thereby promoting β-catenin-dependent transcription (Fig. 2) (Heallen et al., 2011, Rosenbluh et al., 2012). On the other hand, DVL is an elementary factor in transducing the signal from a Wnt ligand binding to one of its receptors and thereby facilitates the Wnt/β-catenin pathway. Cytoplasmic presence of YAP sequesters DVL in the cytoplasm, thereby suppressing Wnt signaling (Barry et al., 2013, Varelas et al., 2010). Thus, it is reasonable to suggest that cytoplasmic YAP functions as an inhibitor of β-catenin, whereas nuclear YAP functions as a positive modulator of β-catenin-dependent transcription (Azzolin et al., 2014), suggesting that β-catenin might also play a role in mechanotransduction. As discussed earlier, 15 undergoing EMT show downregulation of adherens junctions and the junctional protein E-cadherin. The molecular pathways that are activated upon E-cadherin loss are not adequately understood. However, disruption of adherens junctions can lead to nuclear accumulation of the adherens junctional component β-catenin (Coluccia et al., 2006, Koenig et al., 2006, Morali et al., 2001, Onder et al., 2008). β-catenin, in addition to its role in stabilizing adherens junctions, also functions as the primary mediator of the canonical Wnt pathway, an important developmental and oncogenic pathway (Clevers & Nusse, 2012). Regulation of Wnt signaling and the molecular machinery involved have multiple degrees of complexity and describing these in detail, is far beyond the scope of this review. It is important to note, that free cytosolic β-catenin is rapidly degraded by a multiprotein destruction complex when this pathway is off. However, once turned on, the destruction complex is disrupted, allowing β-catenin to translocate to the nucleus. Inside the nucleus, β-catenin acts as a transcriptional co-activator by associating with several transcription factors, most prominently to the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors. Nuclear translocation and induction of β-catenin-dependent gene transcription are often associated with enhanced tumor progression (Clevers & Nusse, 2012). Interestingly, translocation of β-catenin can also occur independent of Wnt signaling. In this regard, studies focusing on the inflammatory mediator prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2), which is often found overexpressed in carcinomas, are of particular interest. By binding to E-type prostanoid (EP) receptors, PGE2 exerts it effects on cell behavior. The different EP receptors, EP1-4, are GPCRs that couple to distinct intracellular pathways based on the G-protein they associate with. It is now widely recognized that PGE2 promotes tumor progression (Buchanan et al., 2006, Kim et al., 2011, Wang and Dubois, 2006). Importantly, downstream of PGE2 binding to its receptors β-catenin and TCF-dependent transcriptional programs can be activated (Castellone et al., 2005, Ho et al., 2013, Shao et al., 2005), through a mechanism involving cyclic AMP (Brudvik et al., 2011, Jansen et al., 2015, Shao et al., 2005). In endothelial cells, the cyclic AMP regulated GEF Epac1 can function as an atypical GEF for Rac1, downstream of PGE2 (Birukova et al., 2007, Birukova et al., 2010, Maillet et al., 2003). Recent studies performed by our group on the role of β-catenin in EMT and migration of NSCLC cells, have further identified the involvement of the cyclic AMP regulated GEF Epac1 (Jansen et al., 2016). Herein, we show that PGE2 induces EMT, nuclear β-catenin accumulation and transcription of β-catenin target genes. Downregulation, pharmacological inhibition, or expression of a mutant Epac1 with a defunct nuclear pore localization signal (Parnell, Smith, & Yarwood, 2015), abolishes the effects of PGE2 on either β-catenin or EMT. Although we have not yet elaborated on the exact molecular mechanisms by which Epac1 is involved in β-catenin-dependent transcription, we anticipate that there is a critical involvement of Rho proteins (Fig. 2). Activation of Rac1 has been recognized as a driving factor in β-catenin stabilization, nuclear import, and target gene transcription (Fig. 2) (Wu et al., 2008). Although the underlying mechanisms leading to the nuclear β-catenin by Rac1 are not fully understood, it has been proposed that Rac1 facilitates nuclear import of β-catenin (Esufali & Bapat, 2004), thus openening up the possibility that PGE2 promotes nuclear import through a mechanism involving Epac1-mediated activation of Rac1.