The Role of Plakophilin 3 in Keratinocyte Biology

描述(申请人提供)：血小板亲和素3(PKP3)是一种桥粒蛋白，属于细胞黏附和信号转导蛋白家族中的一种。我们的初步数据表明，表皮角质形成细胞中Pkp3功能的丧失会导致几种螳螂蛋白(蛋白亲和素1、蛋白球蛋白、β-连环蛋白)的上调，细胞迁移减少，对癌基因介导的转化的敏感性增加。因此，我们得出结论，PKP3在复层上皮细胞中作为肿瘤抑制基因发挥作用。我们的数据为观察到的PKP3下调与人类鳞癌恶性程度增加之间的相关性提供了一个机制解释。我们还发现PKP3与G3BP和Rack-1蛋白相互作用，这些蛋白被认为调节细胞应激反应，如热或化学应激下细胞的死亡和细胞生存决定。该项目的成功完成将导致在角质形成细胞中发现新的细胞信号通路，这些信号通路对细胞应激反应、细胞迁移和角质形成细胞对肿瘤发展的敏感性至关重要。 公共卫生相关性：健康相关性本项目的目标是确定桥粒细胞黏附和信号蛋白亲板素3(PKP3)在皮肤角质形成细胞对癌基因介导的肿瘤形成的易感性中的作用。我们还将评估PKP3在细胞迁移和角质形成细胞应激反应中的作用，即与皮肤肿瘤形成和进展相关的过程。

DESCRIPTION (provided by applicant): Plakophilin 3 (PKP3) is a desmosomal protein that belongs to the armadillo family of cell adhesion and signaling proteins. Our preliminary data demonstrate that loss of Pkp3 function in epidermal keratinocytes leads to an up regulation of several armadillo proteins (plakophilin 1, plakoglobin, ¿-catenin), reduced cell migration and an increased susceptibility to oncogene-mediated transformation. Consequently, we concluded that PKP3 acts as a tumor suppressor gene in stratified epithelia. Our data provide a mechanistic explanation for the observed correlation between PKP3 downregulation and increased malignancy observed in human squamous cell carcinomas. We also found that PKP3 interacts with G3BP and Rack-1 proteins that are thought to regulate cellular stress response, such as cell death and cell survival decisions in cells exposed to heat or chemical stress. The successful completion of this project will lead to the identification of novel cell signaling pathways in keratinocytes that are important for the cellular stress response, cell migration and the susceptibility of keratinocytes to tumor development. PUBLIC HEALTH RELEVANCE: Health Relevance The goal of this project is to characterize the role of the desmosomal cell adhesion and signaling protein plakophilin 3 (PKP3) in the susceptibility of skin keratinocyte to oncogene-mediated tumor formation. We will also assess the role of PKP3 in cell migration and in the stress response of keratinocytes, i.e. processes with relevant to skin tumor formation and progression.