The Role of Plakophilin 3 in Keratinocyte Biology

Plakophilin 3 在角质形成细胞生物学中的作用

• 批准号: 8145421
• 负责人: Peter J. Koch
• 金额: $ 16.97万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145421
• 关键词: Adhesions; Affect; Binding Proteins; Biology; Cell Adhesion; Cell Adhesion Molecules; Cell Death; Cell Survival; Cell physiology; Cell-Cell Adhesion; Cells; Cellular Stress; Cellular Stress Response; Chemicals; Complex; Cytoplasmic Granules; Data; Defect; Development; Down-Regulation; Exposure to; Family; Family Dasypodidae; Goals; Health; Heating; Human; Immigration; In Vitro; Lead; Link; Malignant Neoplasms; Mammalian Cell; Mediating; Mus; Oncogenes; Oncogenic; Pathway interactions; Phenotype; Play; Predisposition; Process; Property; Protein Isoforms; Protein Kinase C; Proteins; Regulation; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Protein; Skin; Skin Neoplasms; Squamous cell carcinoma; Stratified Epithelium; Stress; Testing; Tumor Suppressor Genes; Tumor Suppressor Proteins; Ultraviolet Rays; Up-Regulation; armadillo proteins; biological adaptation to stress; carcinogenesis; cell motility; cell transformation; cell type; hazard; in vivo; keratinocyte; migration; mouse model; mutant; novel; plakoglobin; plakophilins; polypeptide D6; protein expression; protein function; reconstitution; research study; response; tumor; tumor initiation; tumor progression; tumorigenesis

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.

描述（由适用提供）：plakophilin 3（PKP3）是一种脱染色体蛋白，属于细胞粘附和信号传导蛋白家族。我们的初步数据表明，表皮角质形成细胞中PKP3功能的丧失会导致对几种Armadillo蛋白（plakophilin 1，Plakoglobin，�-Catenin）的加强调节，可降低细胞迁移，并增加对Oncogene介导的转化的易感性。因此，我们得出的结论是，PKP3在分层上皮中充当肿瘤抑制基因。我们的数据为观察到的PKP3下调和在人类鳞状细胞癌中观察到的恶性肿瘤增加的相关性提供了一种机械解释。我们还发现，PKP3与G3BP和RACK-1蛋白相互作用，这些蛋白被认为可以调节细胞应激反应，例如暴露于热或化学应激的细胞中细胞死亡和细胞存活决策。该项目的成功完成将导致在角质形成细胞中新型细胞信号通路的鉴定，这对于细胞应激反应，细胞迁移和角质形成细胞对肿瘤发育的敏感性很重要。 公共卫生相关性：健康相关性该项目的目的是表征脱骨细胞粘附和信号传导蛋白质plakophilin 3（PKP3）在皮肤角质形成细胞对癌基因介导的肿瘤形成的敏感性中的作用。我们还将评估PKP3在细胞迁移和角质形成细胞的压力反应中的作用，即与皮肤肿瘤形成和进展有关的过程。