MOLECULAR GENETICS OF TYROSINE KINASE AND RAS FUNCTION

酪氨酸激酶和 RAS 功能的分子遗传学

• 批准号: 2163560
• 负责人: MICHAEL A SIMON
• 金额: $ 19.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2163560
• 关键词: Drosophilidae; biological signal transduction; cell differentiation; cell growth regulation; gene expression; gene induction /repression; genetic enhancer element; genetic mapping; genetic regulation; in situ hybridization; laboratory rabbit; molecular cloning; protein structure function; protein tyrosine kinase; protooncogene; restriction fragment length polymorphism

Protein Tyrosine Kinases (PTKs) are important cellular regulators whose activation can control cellular metabolism (e.g., the insulin receptor), differentiation (the CSF-1 receptor), and growth (PDGF and EGF receptors). The goal of the proposed research is to understand how PTKs have these effects on cells. We are addressing this issue by studying the action of a particular receptor PTK, the product of the sevenless gene of Drosophila melanogaster. The activation of the sevenless PTK serves as a switch that causes a single cell within each unit of the Drosophila compound eye to develop as a photoreceptor rather than as a lens-secreting cell. Our approach is to identify essential components of the sevenless signaling pathway by isolating and characterizing mutations that attenuate signaling by the sevenless PTK. These studies have led to the identification of seven genetic loci (called Enhancers of sevenless) that are candidates to encode proteins that act in sevenless signaling pathway. We have molecularly identified two of the Enhancer of sevenless genes. One, Rasl, is the Drosophila homologue of the H-ras gene of vertebrates. The other, Son of Sevenless (Sos), encodes a putative guanine nucleotide exchange factor whose role may be to activate the Rasl protein. Our subsequent studies have demonstrated that the activation of the Rasl protein can bypass the requirement for sevenless activity and have therefore suggested that the activation of the Rasl protein may be the sole essential action of the sevenless PTK. The goal of the proposed research is to further characterize the sevenless signaling pathway by: 1) molecularly characterizing additional Enhancer of sevenless genes, 2) asking whether the Sos protein is an activator of nucleotide exchange by the Rasl protein, and if so, whether Sos protein activity is regulated by the sevenless PTK, and 3) genetically identifying and molecular characterizing loci that encode components of the Rasl effector pathway. The ability of PTKs to regulate crucial cell processes suggests that an understanding of PTK signal transduction pathways will provide insight into the basic control mechanisms that regulate cell division, metabolism and differentiation. Furthermore, the well-documented involvement of PTKs and ras proteins in the etiology of cancer suggests that understanding the pathways that PTKs and ras proteins use to regulate cellular events will shed light on how inappropnate activation of these proteins can contribute to neoplastic transformation.

蛋白酪氨酸激酶 (PTK) 是重要的细胞调节因子，其 激活可以控制细胞代谢（例如胰岛素受体）， 分化（CSF-1 受体）和生长（PDGF 和 EGF 受体）。 拟议研究的目标是了解 PTK 如何 对细胞有这些影响。 我们正在通过研究来解决这个问题 特定受体 PTK 的作用，PTK 是七者的产物 果蝇的基因。 Sevenless PTK 的激活充当一个开关，导致 果蝇复眼每个单位内的单个细胞发育为 光感受器而不是晶状体分泌细胞。 我们的方法是 通过以下方式识别七次信号通路的重要组成部分 分离和表征减弱信号传导的突变 无七PTK。 这些研究已确定了七种 候选基因位点（称为 Sevenless 增强子） 编码在七次信号通路中起作用的蛋白质。 我们有 分子鉴定了七个基因的两个增强子。 一， Rasl，是脊椎动物 H-ras 基因的果蝇同源物。 这 另一个，七少之子（Sos），编码一个假定的鸟嘌呤核苷酸 交换因子，其作用可能是激活 Rasl 蛋白。 我们的 随后的研究表明 Rasl 的激活 蛋白质可以绕过七活性的要求并具有 因此表明Rasl蛋白的激活可能是 七无 PTK 的唯一基本行动。 拟议研究的目标是进一步表征 七无信号通路通过：1）分子表征额外 七无基因的增强子，2）询问 Sos 蛋白是否是 Rasl 蛋白的核苷酸交换激活剂，如果是，是否 Sos 蛋白活性受七少 PTK 调节，3) 基因识别和分子特征编码位点 Rasl 效应通路的组成部分。 PTK 调节关键细胞过程的能力表明 了解 PTK 信号转导途径将提供深入见解 进入调节细胞分裂、新陈代谢的基本控制机制 和差异化。 此外，有据可查的参与 癌症病因学中的 PTK 和 ras 蛋白表明 了解 PTK 和 ras 蛋白用于调节的途径 细胞事件将揭示这些细胞的不适当激活是如何发生的 蛋白质可以促进肿瘤转化。