ADAPTOR PROTEINS AND MALIGNANT TRANSFORMATION

衔接蛋白和恶性转化

• 批准号: 2895949
• 负责人: DOUGLAS S TYLER
• 金额: $ 7.69万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895949
• 关键词: athymic mouse; binding proteins; biological signal transduction; breast neoplasms; colorectal neoplasms; guanine nucleotide binding protein; immunocytochemistry; immunoprecipitation; lung neoplasms; metastasis; molecular chaperones; neoplastic cell; neoplastic transformation; northern blottings; oncogenes; oncoproteins; phosphorylation; protein binding; protein protein interaction; protein structure function; protein tyrosine kinase; tissue /cell culture; transfection; western blottings

DESCRIPTION (Applicant's Description): The objective of this project is to define the role of adaptor proteins in malignant transformation. Adaptor proteins are unique signaling molecules which, although devoid of any intrinsic enzymatic activity, function mainly by allowing the interconnection of other molecules in various signaling pathways through protein- protein interactions. While mutation of adaptor proteins in the laboratory can cause cells to develop malignant characteristics, a similar process appears to occur in vivo through adaptor protein interactions with various oncogenic proteins. The specific hypothesis of this project is that alteration of adaptor proteins by oncogenic tyrosine kinases is an important mechanism by which oncogenes induce malignant transformation. This project will focus on the adaptor protein CRKL which is constitutively expressed in a number of hematopoietic and non-hematopoietic cells in an unphosphorylated state. Cells which contain the BCR-ABL oncogenic tyrosine kinase, seen in all leukemic cells containing the Philadelphia-1 chromosome abnormality, express high levels of phosphorylated CRKL. The facts that CRKL binds directly to BCR-ABL, that CRKL is the most prominent tyrosine phosphorylated protein in BCR-ABL positive cells, and that significant CRKL phosphorylation occurs only in cells which express BCR-ABL are strongly suggestive that alteration of this adaptor protein through phosphorylation plays a unique role in the malignant transformation of BCR-ABL positive cells. Using several mutated forms of the CRKL protein, the specific alms of this study will be: 1) To define the role of CRKL in malignant transformation induced by BCR-ABL by determining the role of CRKL tyrosine phosphorylation in the oncogenic process and whether downstream effectors and signal transduction pathways utilized by CRKL are affected by CRKL phosphorylation; 2) To determine if CRKL in any form is transforming in the absence of BCR-ABL and develop a model of how CRKL functions with regard to its own phosphorylation; 3) To explore the role of CRKL in other solid tumor systems like lung cancer, breast cancer, and colorectal cancer which have been associated with alterations in tyrosine kinase signaling pathways.

描述（申请人的描述）： 该项目的目的是定义衔接蛋白在 恶性转化。 适配器蛋白是独特的信号分子 尽管没有任何固有的酶活性，但主要功能主要是 通过允许其他分子在各种信号中的互连 通过蛋白质相互作用的途径。 而适配器的突变 实验室中的蛋白质会导致细胞发展恶性肿瘤 特征，通过适配器在体内似乎发生了类似的过程 蛋白质与各种致癌蛋白的相互作用。 具体 该项目的假设是通过 致癌酪氨酸激酶是一种重要的机制 诱导恶性转化。 该项目将重点放在适配器蛋白CRKL上 在许多造血和非山摩托克细胞中表达 未磷酸化状态。 包含BCR-ABL致癌酪氨酸的细胞 激酶，在所有含有费城1染色体的白血病细胞中可见 异常，表达高水平的磷酸化CRKL。 事实 CRKL直接与BCR-ABL结合，该CRKL是最突出的酪氨酸 BCR-ABL阳性细胞中的磷酸化蛋白质，并且显着的CRKL 磷酸化仅发生在表达BCR-ABL的细胞中 暗示通过磷酸化改变该衔接蛋白 在BCR-ABL阳性的恶性转化中起着独特的作用 细胞。 使用几种突变形式的CRKL蛋白，这是其中的特定施舍 研究将是：1）定义CRKL在恶性转化中的作用 通过确定CRKL酪氨酸磷酸化的作用，由BCR-ABL诱导 在致癌过程以及下游效应子和信号是否 CRKL使用的转导途径受CRKL磷酸化的影响； 2）确定在没有任何形式的情况下是否在不存在的情况下转换 BCR-ABL并开发了CRKL如何发挥作用的模型 磷酸化； 3）探索CRKL在其他实体瘤系统中的作用 像肺癌，乳腺癌和结直肠癌一样 与酪氨酸激酶信号通路的改变有关。