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。它是常见的转移是一个主要贡献者的发病率和死亡率与癌症相关。为了使细胞离开原发肿瘤并迁移到远处，人们认为它们必须调节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。钙粘蛋白是一种跨膜蛋白，聚集在细胞-细胞粘附的位点，称为粘附连接。上皮组织中最常见的钙粘蛋白是e -钙粘蛋白。在上皮细胞向间质细胞转化的过程中，e -钙粘蛋白的功能经常下调。有时这是由信使rna或蛋白质合成减少引起的。在其他情况下，E-cadherin的功能可以丧失，但表达没有明显变化。e -钙粘蛋白功能的关键调节因子是一种叫做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。我们发现p120-连环蛋白在一个半胱氨酸残基上棕榈酰化。在这里描述的研究中，我们建议鉴定将棕榈酸酯添加到p120-连环蛋白中的酶和去除它的酶。了解相关的酶可能提供通过改变p120-连环蛋白棕榈酰化状态来改变E-cadherin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 -钙粘蛋白介导的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用于预防或治疗转移。