ADHESION JUNCTION REGULATION IN NORMAL AND DISEASED SKIN

正常和患病皮肤的粘附连接调节

基本信息

批准号：
6653046
负责人：
DAVID S RUBENSTEIN
金额：
$ 25.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2006-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6653046
关键词：
Drosophilidae cadherins cell adhesion cell adhesion molecules glycosylation glycosyltransferase intercellular connection keratinocyte laboratory rabbit molecular pathology pathologic process phosphorylation tissue /cell culture

项目摘要

DESCRIPTION: (Verbatim) The human proteins beta catenin and plakoglobin, and the related Drosophila protein Armadillo, have dual roles in keratinocyte cell-cell adhesion and in mediating cellular signaling events. Aberrant regulation of these proteins plays a role in both human cancers and cutaneous autoimmune disease. Beta catenin's signaling function is constitutively activated in a variety of human cancers including colorectal carcinoma and melanoma. In the desmosome, plakoglobin binds desmoglein 3 and 1, the target antigens for autoantibodies produced in the autoimmune blistering diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF), respectively. Since human beta catenin and plakoglobin and Drosophila Armadillo are phosphoproteins, phosphorylation may represent one mechanism by which these proteins are post-translationally regulated. In addition, we have recently identified O-glycosylation as a second post-translational modification of this family of proteins. We have cloned the Drosphila 0-glycosyltransferase (OGT) gene whose protein product is responsible for catalyzing the addition of this modification in vivo; the Drosophila OGT gene is 80 percent identical to the human counterpart. Over expression of this gene in Drosophila provides us with a tool to explore how this new modification affects the in vivo biology of these proteins. Because of the high degree of identity between (1) the Drosophila and human OGTs and (2) Drosophila Armadillo and human beta catenin and plakoglobin, we can directly apply what we learn from genetic and biochemical studies of the fly to human biology. We test what we learn from the fly by biochemical and cell biologic analyses in a normal human keratinocyte tissue culture system. This proposal details our plan to investigate how the cell-cell adhesion and signal transduction functions of human beta catenin and plakoglobin and Drosophila Annadillo are regulated by (1) phosphorylation and (2) O-glycosylation. Once these processes are disclosed, we believe that we may be able to understand the molecular mechanisms of acantholysis in the human autoimmune blistering diseases pemphigus vulgaris and pemphigus foliaceus.

描述：（逐字记录）人类蛋白质 β 连环蛋白和斑珠蛋白，以及相关的果蝇蛋白犰狳，在角质形成细胞中具有双重作用细胞间粘附和介导细胞信号传导事件。异常这些蛋白质的调节在人类癌症和皮肤癌中发挥作用自身免疫性疾病。 β连环蛋白的信号传导功能是组成型的在多种人类癌症中被激活，包括结直肠癌和黑色素瘤。在桥粒中，板珠蛋白结合桥粒糖蛋白 3 和 1，即目标蛋白自身免疫性水疱疾病中产生的自身抗体的抗原分别为寻常型天疱疮 (PV) 和落叶型天疱疮 (PF)。由于人类β连环蛋白和斑珠蛋白以及果蝇犰狳是磷酸化可能代表了这些磷蛋白的一种机制蛋白质受到翻译后调节。此外，我们最近还确定 O-糖基化是该蛋白的第二个翻译后修饰蛋白质家族。我们克隆了果蝇0-糖基转移酶（OGT）其蛋白质产物负责催化添加该基因的基因体内修饰；果蝇 OGT 基因与果蝇 80% 相同人类对应物。该基因在果蝇中的过度表达为我们提供了探索这种新修饰如何影响体内生物学的工具这些蛋白质。由于（1）之间的高度同一性果蝇和人类 OGT 以及 (2) 果蝇犰狳和人类 β 连环蛋白和斑珠蛋白，我们可以直接应用我们从遗传和苍蝇的生化研究对人类生物学的影响。我们测试我们从中学到的东西通过正常人角质形成细胞的生化和细胞生物学分析进行飞行组织培养系统。该提案详细介绍了我们的计划，以调查如何人β连环蛋白和细胞间粘附和信号转导功能斑珠蛋白和果蝇 Annadillo 受 (1) 磷酸化和 (2)O-糖基化。一旦这些流程被披露，我们相信我们可以能够了解人类棘层松解症的分子机制自身免疫性水疱病寻常型天疱疮和落叶型天疱疮。