Regulation of Ras-Dependent Signal Transduction Pathways

Ras 依赖性信号转导途径的调节

• 批准号: 7052419
• 负责人: DEBORAH K MORRISON
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7052419
• 关键词: Caenorhabditis elegans; Drosophilidae; biological signal transduction; carcinogenesis; cell growth regulation; cell proliferation; enzyme activity; enzyme induction /repression; gene induction /repression; genetic regulation; guanosinetriphosphatases; mass spectrometry; mitogen activated protein kinase

Ras is a small, evolutionarily conserved GTPase that functions to transmit signals regulating cellular proliferation, differentiation, survival and transformation. Oncogenic Ras proteins, which are constitutively activated forms of Ras, cause inappropriate cell proliferation and are associated with approximately 30% of all human malignancies. Because Ras plays such a critical role in both normal and abnormal growth processes, our laboratory has focused its research on elucidating the components involved in and the mechanisms regulating Ras-dependent signal transduction. Specifically, our studies can be divided into four main areas: 1. Regulation of the Raf family of serine/threonine kinases. The Raf kinase family serves as an essential intermediate in many signaling cascades, functioning to relay signals from activated Ras to the downstream protein kinases MEK and ERK. Moreover, deregulated or constitutively active Raf proteins can themselves cause cell transformation and mutations in the Raf family member B-Raf have been observed in 67% of malignant melanomas as well as in many colorectal, ovarian and papillary thyroid carcinomas. Our goal in this project is to examine the means by which the Raf kinases becomes activated and inactivated during growth, development, and oncogenesis. 2. Function of Kinase Suppressor of Ras (KSR). KSR was discovered to be a positive effector of Ras signaling by genetic studies performed in Drosophila and C. elegans. Our investigation of the mammalian KSR protein has been to determine the specific mechanism(s) by which KSR functions to transduce Ras-dependent signals. 3. Mass spectrometry analysis of Ras pathway components. Several components of the Ras pathway, such as the Raf kinases and the scaffolding proteins KSR, CNK and SUR8, are found in high molecular weight complexes in mammalian cells. To identify the constituents of these complexes and to isolate other potential regulators of the Ras pathway, our laboratory has begun a comprehensive analysis of these protein complexes utilizing the NCI mass spectrometry facility. 4. Ras signaling pathways in Drosophila. Due to the complex nature of cellular signal transduction, our laboratory has had an ongoing interest in using Drosophila as a model system for studying signaling events. We are currently using this system to identify novel proteins involved in Ras-dependent signal transduction.

Ras是一种小的、进化上保守的GT3，其功能是传递调节细胞增殖、分化、存活和转化的信号。致癌性Ras蛋白是Ras的组成性激活形式，引起不适当的细胞增殖，并与约30%的人类恶性肿瘤相关。由于Ras在正常和异常生长过程中起着至关重要的作用，我们实验室的研究重点是阐明Ras依赖的信号转导所涉及的成分和调节机制。具体而言，我们的研究可以分为四个主要方面：1。丝氨酸/苏氨酸激酶的Raf家族的调节。Raf激酶家族在许多信号级联中充当必需的中间体，起到将信号从活化的Ras传递到下游蛋白激酶MEK和ERK的作用。此外，失调或组成型活性Raf蛋白本身可引起细胞转化，并且在67%的恶性黑素瘤以及许多结直肠癌、卵巢癌和乳头状甲状腺癌中观察到Raf家族成员B-Raf的突变。我们在这个项目中的目标是研究Raf激酶在生长、发育和肿瘤发生过程中被激活和失活的方式。2. Ras激酶抑制因子（KSR）的功能在果蝇和果蝇中进行的遗传学研究发现KSR是Ras信号传导的正效应子。优美的我们对哺乳动物KSR蛋白质的研究旨在确定KSR对Ras依赖性信号起作用的具体机制。3. Ras途径组分的质谱分析。Ras途径的几种组分，如Raf激酶和支架蛋白KSR、CNK和SUR 8，在哺乳动物细胞中的高分子量复合物中发现。为了鉴定这些复合物的成分并分离Ras途径的其他潜在调节剂，我们的实验室已经开始利用NCI质谱设施对这些蛋白质复合物进行全面分析。4.果蝇的Ras信号通路。由于细胞信号转导的复杂性，我们的实验室一直有兴趣使用果蝇作为研究信号事件的模型系统。我们目前正在使用这个系统，以确定新的蛋白质参与Ras依赖的信号转导。