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

Plakophilin 1是细胞接触蛋白的犰狳家族的成员，其在调节桥粒粘附中具有重要功能。由于其相当大的细胞质和核池，已经假设斑嗜蛋白可能具有类似于β-连环蛋白的信号传导功能。我们最近已经证明，plakophilin 1刺激翻译在体内和体外通过直接与真核翻译起始因子eIF 4A 1的相互作用。Plakophilin 1是帽结合eIF 4F复合物的一部分，并促进eIF 4A 1和eIF 4 B募集到帽结合复合物中，从而刺激翻译。这与增殖和细胞大小的增加相关。 在拟议的项目中，我们的目标是表征如何在体内调节plakophilin 1-桥粒和细胞质池之间的平衡，以及这如何影响细胞间的粘附，翻译和增殖。初步证据支持了由核糖体S6激酶（S6 K）和AKT激酶引起的斑嗜蛋白1磷酸化的作用。这将详细描述，并将研究生理相关性。

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.