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  • br Presenilins and Wnt catenin signalling

    2022-01-17


    Presenilins and Wnt/β-catenin signalling Several groups have provided substantial data indicating that PS1 acts as a negative modulator of the transcriptional activity of the β-catenin/Tcf-4 complex (Fig. 4) [120], [121], [122]. β-Catenin is a multifunctional protein that was first described as a mediator of cadherin-dependent cell adhesion. In adherens junctions β-catenin and the related protein γ-catenin (plakoglobin) are required for recruiting the PG 01037 dihydrochloride receptor cytoskeleton. In addition to its function in cell adhesion, β-catenin is also central to the Wnt signalling pathway. Therefore, β-catenin is a signalling protein that links transmembrane adhesion proteins, such as the γ-secretase substrate E-cadherin [123], with intracellular signalling pathways and is involved in regulating transcription in a number of anti-apoptotic/survival pathways [124]. When released from the junction complex β-catenin can accumulate in the cytosol and translocate to the nucleus, where it interacts with the Tcf-family of transcription factors and positively regulates expression of several genes involved in development and tumorigenesis. The translocation of β-catenin to the nucleus is controlled by a GSK-3β contained protein complex that regulates the phosphorylation, ubiquitination and degradation of β-catenin [125]. Wnt signalling antagonizes the activity of the degradation complex, which promotes the stabilization and nuclear translocation of β-catenin [126], [127]. Early studies identified the presenilins as binding partners for GSK-3β and subsequent works identified three conserved GSK-3β consensus phosphorylation sequences in PS1 and characterized PS1 as an unprimed substrate of GSK-3β [128]. Phosphorylation of PS1 at one of these GSK3β sites (amino acids 353–357) located regulates the interaction between PS1 and β-catenin and phosphorylation at a second site (amino acids 397–401) modulated the stability and degradation of PS1 CTF [129], [130]. Phosphorylation by GSK-3β at Ser353 and Ser357 has also been shown to reduce the association of PS1, N-cadherin and β-catenin and a decrease in this association negatively affects Akt signalling [58]. While extensive biochemical data exists supporting a role for presenilins in Wnt/β-catenin signalling, research have proposed numerous mechanisms to support this role, including the interaction of PS1 with E- and N-cadherin and β-catenin and γ-secretase activity [120], [131]. It was not until recently that PS1 has been conclusively shown to have both γ-secretase-dependent and -independent roles in β-catenin mediated transcription, where the PS1 holoprotein and the processed PS1 NTF/CTF heterodimers have contrasting roles in modulating β-catenin/Tcf-4 gene transcription [37]. Earlier studies had shown that PS1 FAD mutants inhibit Wnt signalling by increasing β-catenin phosphorylation and degradation [132], and to induce apoptosis in neuronal cells [34]. Additionally, defects in neurite growth observed in FAD murine cells can be reduced by inhibition of β-catenin mediated gene transcription [133]. Others demonstrated that Drosophila presenilin (DPS) negatively regulated Wnt signalling [122], and that loss of DPS expression resulted in cytosolic accumulation of armadillo/β-catenin [134]. Consistent with this, conditional knockout of PS1 in keratinocytes resulted in enhanced β-catenin/Tcf signalling and skin tumorigenesis [121]. Some researchers proposed that the enhanced β-catenin/Tcf signalling in presenilin-deficient cells resulted from the delocalization of GSK-3β from the cytoplasm to the endosome [94]. In subsequent studies it has been demonstrated that the inhibitor effect of PS1 holoprotein on β-catenin signalling does not depend on the proteolytic activity of PS1/γ-secretase or on the destabilization of β-catenin [135], but rather a physical interaction between PS1 holoprotein and γ-catenin (plakoglobin) and Tcf-4. Furthermore it was demonstrated that negative effect of PS1 NTF/CTF heterodimers on β-catenin/Tcf-4 transcription was dependent upon γ-secretase activity and proteolysis of E- or N-cadherin and the generation of ICDs, which resulted in destabilization of the β-catenin transcriptional cofactor CBP [37]. In summary, extensive evidence exists to support a γ-secretase independent role for presenilins in Wnt/catenin signalling, however, given that presenilins not only associates with cadherin/catenin complexes, but γ-secretase also cleaves E-cadherin and N-cadherin adds complexity to deciphering the precise regulatory role of presenilins in Wnt signalling [123], [131].