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（由申请人提供）：大多数人类癌症是上皮组织的癌症，称为癌。转移通常是癌症相关发病率和死亡率的主要原因。为了让细胞离开原发肿瘤并迁移到远处，人们认为它们必须调节其识别邻近细胞的能力。钙粘蛋白家族的蛋白质是细胞间识别机制的主要组成部分。钙粘蛋白是跨膜蛋白，聚集在称为粘附连接的细胞-细胞粘附位点。上皮组织最常见的钙粘蛋白是E-钙粘蛋白。在上皮-间质转化过程中，E-钙粘蛋白的功能经常下调。有时这是由 mRNA 或蛋白质合成减少引起的。在其他情况下，E-钙粘蛋白的功能可能会丧失，而表达却没有显着变化。 E-钙粘蛋白功能的关键调节因子是 p120-连环蛋白。棕榈酰化是一种可逆的翻译后修饰，可以显着改变蛋白质与膜的相互作用方式。我们发现 p120-连环蛋白在单个半胱氨酸残基处被棕榈酰化。在此描述的研究中，我们建议鉴定向 p120-连环蛋白添加棕榈酸酯的酶以及将其去除的酶。了解所涉及的酶可能会提供通过改变 p120-连环蛋白的棕榈酰化状态来改变 E-钙粘蛋白功能的方法。我们还建议在模型系统中进行研究，以进一步了解 p120-连环蛋白的棕榈酰化如何影响 E-钙粘蛋白介导的细胞-细胞粘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。