Studies on Cadherin/Catenin Complexes

钙粘蛋白/连环蛋白复合物的研究

• 批准号: 8883453
• 负责人: KEITH R JOHNSON
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883453
• 关键词: Address; Adherens Junction; Affect; Behavior; Binding; Biochemical; Biochemistry; Biological; Biological Models; Cadherins; Carcinoma; Cell Adhesion; Cell Adhesion Molecules; Cell model; Cell surface; Cell-Cell Adhesion; Cells; Cellular Structures; Cellular biology; Complex; Cysteine; Data; Desmosomes; Disease; Distant; Down-Regulation; E-Cadherin; Enzymes; Epithelial; Epithelial Cells; Extracellular Domain; Family; Family member; Genetic Transcription; Goals; Health; Human; Integral Membrane Protein; Intercellular Junctions; Left; Malignant Neoplasms; Mediating; Membrane; Mesenchymal; Messenger RNA; Methods; Modeling; Modification; Molecular Conformation; Molecular Structure; Morbidity - disease rate; Neoplasm Metastasis; Palmitates; Palmitic Acylation Site; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phenotype; Play; Post-Translational Protein Processing; Primary Neoplasm; Process; Proteins; Regulation; Research Personnel; Roentgen Rays; Role; Signal Transduction; Site; Snails; Tail; Tissues; Transferase; base; cancer cell; carcinogenesis; desmocollin; desmoglein; desmoplakin; epithelial to mesenchymal transition; esterase; extracellular; member; mortality; mutant; overexpression; palmitoylation; polypeptide D6; prevent; transcription factor

DESCRIPTION (provided by applicant): The majority of human cancers are cancers of epithelial tissues called carcinomas. It is common for metastases to be a major contributor to the morbidity and mortality associated with carcinomas. In order for cells to leave the primary tumor and migrate to distant sites, it is thought they must modulate their ability to recognize neighboring cells. Proteins of the cadherin family are major components of the cell-cell recognition machinery. Cadherins are transmembrane proteins that cluster at sites of cell-cell adhesion called adherens junctions. The cadherin most common to epithelial tissues is E-cadherin. During the process of epithelial-to- mesenchymal transition, the function of E-cadherin is frequently down regulated. Sometimes this is caused by decreased synthesis of the mRNA or protein. In other cases, the function of E-cadherin can be lost without significant change in expression. A critical regulator of E-cadherin function is the protein called p120-catenin. Palmitoylation is a reversible post-translational modification that can significantly change how proteins interact with membranes. We have found that p120-catenin is palmitoylated at a single cysteine residue. In the studies described here, we propose identifying the enzymes that add palmitate to p120-catenin and the enzymes that remove it. Knowing the enzymes involved may offer methods of altering E-cadherin function by altering the palmitoylation status of p120-catenin. We also propose studies in model systems to further our understanding how the palmitoylation of p120-catenin affects the biochemistry and cell biology of E-cadherin-mediated cell- cell adhesion. Our long term goal is to determine if modulating this aspect of p120-catenin can be used to prevent or treat metastases.

描述(申请人提供)：大多数人类癌症是上皮组织癌，称为癌。转移瘤通常是癌症相关发病率和死亡率的主要因素。为了让细胞离开原发肿瘤并迁移到遥远的地方，人们认为它们必须调节自己识别邻近细胞的能力。钙粘蛋白家族的蛋白质是细胞-细胞识别机制的主要组成部分。钙粘附素是一种跨膜蛋白，聚集在细胞与细胞之间的粘连部位，称为粘连连接。上皮组织中最常见的钙粘附素是E-钙粘附素。在上皮向间充质转化的过程中，E-钙粘附素的功能经常下调。有时这是由于信使核糖核酸或蛋白质合成减少所致。在其他情况下，E-钙粘附素的功能可能会在表达没有显著变化的情况下丧失。E-钙粘附素功能的一个关键调节因子是一种名为p120-连环蛋白的蛋白质。棕榈酰化是一种可逆的翻译后修饰，可以显著改变蛋白质与膜的相互作用方式。我们发现，p120-catenin是在一个半胱氨酸残基上棕榈酰化的。在这里描述的研究中，我们建议确定将棕榈酸添加到p120-连环蛋白中的酶以及移除它的酶。了解与之相关的酶可能提供通过改变p120-catenin的棕榈酰化状态来改变E-钙粘素功能的方法。我们还建议在模型系统中进行研究，以进一步了解p120-catenin的棕榈酰化如何影响E-钙粘附素介导的细胞-细胞黏附的生物化学和细胞生物学。我们的长期目标是确定调节p120-连环蛋白的这一方面是否可以用于预防或治疗转移。