Plakophilin-3 Catenin Associates with the ETV1/ER81 Transcription Factor to Positively Modulate Gene Activity

Abstract

Members of the plakophilin-catenin sub-family (Pkp-1, -2, and -3) facilitate the linkage of desmosome junctional components to each other (e.g. desmosomal cadherins to desmoplakin) and the intermediate-filament cytoskeleton. Pkps also contribute to desmosomal stabilization and the trafficking of its components. The functions of Pkps outside of the desmosome are less well studied, despite evidence suggesting their roles in mRNA regulation, small-GTPase modulation (e.g. mid-body scission) during cell division, and cell survival following DNA damage. Pkp-catenins are further believed to have roles in the nucleus given their nuclear localization in some contexts and the known nuclear roles of structurally related catenins, such as beta-catenin and p120-catenin. Further, Pkp-catenin activities in the nuclear compartment have become of increased interest with the identification of interactions between Pkp2-catenin and RNA Pol III and Pkp1 with single-stranded DNA. Consistent with earlier reports suggesting possible nuclear roles in development, we previously demonstrated prominent nuclear localization of Pkp3 in Xenopus naïve ectoderm (“animal cap”) cells and recently resolved a similar localization in mouse embryonic stem cells. Here, we report the association and positive functional interaction of Pkp3 with a transcription factor, Ets variant gene 1 (ETV1), which has critical roles in neural development and prominent roles in human genetic disease. Our results are the first to report the interaction of a sequence-specific transcription factor with any Pkp. Using Xenopus laevis embryos and mammalian cells, we provide evidence for the Pkp3:ETV1 complex on both biochemical and functional levels.

Beyond β-catenin: prospects for a larger catenin network in the nucleus

“…Intriguingly, plakophilin 3 binds to the transcription factor ETS translocation variant 1 (ETV1; also known as ER81) 111 , which is an ETS family member that has crucial roles in dopaminergic neural development. Plakophilin 3 also associates with the closely related ETV5.…”

Hematopoietic plakophilin‐3 regulates acute tissue‐specific and systemic inflammation in mice

“…Although not previously linked to proinflammatory mRNAs, similar activation mechanisms have been described for members of the plakophilin protein family. Indeed, PKP3 was shown to activate transcription via interaction with transcription factor ETV1 [20], PKP1 and PKP3 can stabilize mRNA when they are present in mRNA ribonucleoprotein particles [27], and PKP1 interacts with the eukaryotic translation initiation factor 4A1 (eIF4A1), thereby stimulating translation [42]. The observed PKP3-dependent transcriptional activation or RNA stabilization of proinflammatory cytokines in isolated neutrophils is seemingly in contrast to the increased systemic cytokine levels and sensitivity of the PKP3 −/− and PKP3 −/−hem mice in the different inflammatory mouse models.…”

“…Plakophilin-3 (PKP3) is a member of the p120ctn subfamily of armadillo proteins, which comprises adaptor proteins involved in the regulation of cell−cell adhesion, morphogenesis, homeostasis, and tumor development [18][19][20]. PKP3 is predominantly expressed in epithelial tissues and is an important integrator at cell-cell junctions as it contributes to correct maturation of both desmosomes and adherens junctions [18,19,[21][22][23][24].…”

“…PKP3 is predominantly expressed in epithelial tissues and is an important integrator at cell-cell junctions as it contributes to correct maturation of both desmosomes and adherens junctions [18,19,[21][22][23][24]. However, it also has important nonjunctional functions, such as regulating protein synthesis, growth control, and transcription [18][19][20]23]. In the cytoplasm, PKP3 is a constituent of stress granules and other RNA-containing particles that influence the stability of specific mRNAs and thus act as posttranscriptional regulators of gene expression [25][26][27].…”

“…Activation of PRRs stimulates several signaling cascades that culminate in the release of proinflammatory cytokines, chemokines, and mediators that enhance vasodilation and neutrophil extravasation, as well as acquisition of plasma components such as complement and antibodies to destroy pathogens and damaged cells [17]. Additionally, phagocytes are stimulated to clear the noxious agents and further activate inflammation in order to induce pathogen clearance and tissue repair, and restore immune homeostasis.Plakophilin-3 (PKP3) is a member of the p120ctn subfamily of armadillo proteins, which comprises adaptor proteins involved in the regulation of cell−cell adhesion, morphogenesis, homeostasis, and tumor development [18][19][20]. PKP3 is predominantly expressed in epithelial tissues and is an important integrator at cell-cell junctions as it contributes to correct maturation of both desmosomes and adherens junctions [18,19,[21][22][23][24].…”