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: 3267197
• 负责人: MICHAEL A SIMON
• 金额: $ 20.05万
• 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/3267197
• 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)是一种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是如何 对细胞有这些影响。我们正在通过研究来解决这个问题 一种特殊的受体PTK的作用，它是Seven less的产物 黑腹果蝇的基因。 Seven less PTK的激活起到了开关的作用，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 通过以下方式确定Svenless信号通路的基本组成部分 分离和鉴定通过以下途径减弱信号的突变 七点式PTK。这些研究已经确定了七个 候选基因座(称为SEVENLESS增强子) 编码在七个信号通路中起作用的蛋白质。我们有 分子鉴定了两个Seven less基因的增强子。一, RASL，是脊椎动物H-ras基因的果蝇同源物。这个 Other，Seven less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 蛋白质可以绕过七星活动的要求，并具有 因此提示，RASL蛋白的激活可能是 Seven less PTK的唯一基本动作。 拟议研究的目标是进一步确定 七条信号通路：1)分子表征附加信号 七种基因的增强子，2)询问SOS蛋白是否是一种 RASL蛋白的核苷酸交换激活剂，如果是，是否 SOS蛋白活性受Seven less PTK调节，以及3) 编码基因的遗传鉴定和分子特征基因座 RASL效应器途径的组成部分。 PTKs调节关键细胞过程的能力表明， 对PTK信号转导通路的理解将提供洞察 到调节细胞分裂、新陈代谢的基本控制机制 和差异化。此外，有据可查的参与 PTKs和ras蛋白在癌症病因学中的作用 了解PTKs和ras蛋白用于调节的途径 细胞事件将阐明这些细胞如何被未经批准的激活 蛋白质可以促进肿瘤转化。