It directly affects the phosphorylation state of microtubules and microtubule-associated proteins that regulate microtubule assembly and stability (Hoffman et al., 2017). either directly by associating with and dephosphorylating component proteins, or indirectly by affecting signaling pathways that control junctional integrity and cytoskeletal dynamics. PP2A YO-01027 deregulation has severe consequences on the stability and functionality of these structures, and disruption of cellCcell adhesion and cell polarity likely contribute to the link between PP2A dysfunction and human carcinomas. gene expression is strongly suppressed by expression of polyomavirus small tumor antigen (Klucky et al., 2004). Like SV40 st, this viral protein primarily targets and deregulates PP2A to force quiescent host cells to enter into the S-phase of the cell cycle, thereby allowing viral replication (Garcia et al., 2000). These findings raise the possibility that deregulation of PP2A can also influence cellular levels of OB-cadherin. Lastly, increased expression of P-cadherin (Placental cadherin/cadherin-3/CDH3) has also been described in certain advanced carcinomas, wherein E-cadherin is again characteristically downregulated. It is noteworthy that overexpression of PME-1, an enzyme that YO-01027 demethylates and inactivates PP2A, correlates with the loss of E-cadherin and presence of P-cadherin in aggressive endometrial cancer (Wandzioch et al., 2014). Altogether, these findings suggest the existence of a compelling relationship between deregulation of PP2A, altered expression levels of different cadherins, EMT and metastasis, which merits further investigation. More studies are also necessary to determine whether specific PP2A holoenzymes can directly interact with and regulate cadherins. Mechanistically, the loss of E-cadherin not only leads to the dissociation of the membrane-bound E-cadherin/-catenin complex and disruption of AJs, but also to the activation of major cancer-promoting signaling pathways that upregulate transcription factors linked to EMT (Coopman and Djiane, 2016). Notably, it is associated with alterations in -catenin subcellular localization and increased -catenin dependent transcription. Indeed, this is due to the dual regulatory role of distinct cellular -catenin pools: -catenin not only functions in cell adhesion as part of the stabilized, membrane-associated cadherin/catenin AJ complex, but also in the nucleus as a regulator of gene transcription in the Wnt signaling pathway. The localization of -catenin is dependent on its phosphorylation state. In absence of Wnt YO-01027 signal, cytoplasmic -catenin is constantly phosphorylated and targeted for ubiquitin-mediated proteasomal degradation, as a result of the action of a functional -catenin destruction complex. When dephosphorylated, -catenin translocates from membrane and/or cytoplasmic pools to the nucleus, wherein it controls expression of genes affecting growth, proliferation and apoptosis. Deregulation of the Wnt/-catenin pathway results in an overabundance of nuclear -catenin, and aberrant activation of Wnt/-catenin target genes that promote malignant cell transformation (Jamieson et al., 2012; Thompson and Williams, 2018). Thus, deregulation of -catenin and/or AJs may be problematic in more ways than one. Not only does accumulation of -catenin in the nucleus stimulate carcinogenesis, it also results in the removal of -catenin from the AJ resulting in a loss PLA2B of cellCcell adhesion, thus promoting EMT and metastasis. PP2A isoforms play an important but complex role in the regulation of Wnt signaling (Thompson and Williams, 2018). The PP2A core enzyme is responsible for the rapid dephosphorylation of free, cytoplasmic phospho–catenin (Su et al., 2008). In human pancreatic cancer cells, PP2A inhibition increases -catenin phosphorylation and promotes its degradation (Wu et al., 2014). Likewise, knockdown of PP2A C subunit in cells (Su et al., 2008) and (Gotz et al., YO-01027 2000) results in hyperphosphorylation of -catenin, and excessive degradation of both cytoplasmic and membrane-bound -catenin. In HEK293T and SV480 YO-01027 epithelial cells, the PP2A B (or PPP2R2A) subunit directly binds to the cytoplasmic -catenin associated with the axin complex that functions in Wnt signaling. Overexpression of the PP2A B subunit enhances Wnt signaling, while its knockdown results in -catenin phosphorylation and decreased Wnt signaling (Zhang et al., 2009). In contrast, other studies have implicated PP2A/B holoenzymes as the prevalent regulator.