Regulation of plakophilin1's dual function in translation and desmosome organization

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Plakophilin 1 is a member of the armadillo-family of cell contact proteins that has an essential function in regulating desmosomal adhesion. Due to its considerable cytoplasmic and nuclear pool it has been hypothesized that plakophilins may have a signaling function similar to that of β-catenin. We have recently demonstrated that plakophilin 1 stimulates translation in vivo and in vitro through direct interaction with the eukaryotic translation initiation factor eIF4A1. Plakophilin 1 is part of the cap-binding eIF4F complex and promotes eIF4A1 and eIF4B recruitment into the cap-binding complex thereby stimulating translation. This correlates with an increase in proliferation and cell size. In the proposed project, we aim to characterize how the balance between the plakophilin 1-desmosomal and the cytoplasmic pool is regulated in vivo and how this affects intercellular adhesion, translation and proliferation. Preliminary evidence supports a role of plakophilin 1-phosphorylation by ribosomal S6 kinase (S6K) and AKT kinases. This will be characterized in detail and the physiological relevance will be investigated.