Endomembrane Targeting and Signaling of RAS Proteins

RAS 蛋白的内膜靶向和信号转导

• 批准号: 7803462
• 负责人: Robert J Deschenes
• 金额: $ 4.42万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803462
• 关键词: Proteins; Signal Transduction

DESCRIPTION (provided by applicant): Ras proteins regulate multiple cellular signaling pathways through interaction with an array of effectors including Raf kinases, phosphatidylinositol-3-kinase, Ral GEFs, and Nore1. The best characterized of these regulatory interactions occur on the cytoplasmic surface of the plasma membrane in response to signals from growth factor receptors. However, it is now apparent that Ras also signals from endomembrane compartments and distinct microdomains of the plasma membrane. This has heightened interest in defining the mechanisms of subcellular targeting of Ras and other small monomeric GTPases. We have focused on the subcellular targeting of Ras proteins as a model to understand how lipid modification contributes to protein trafficking and signaling. Ras proteins are posttranslationally modified by CaaX box prenylation (farnesylation), -aaX cleavage, methylation, and with the exception of K-Ras, palmitoylation. Posttranslational modification is required for subcellular targeting, but also plays a key role in the assembly of Ras-dependent signaling complexes in a spatially and temporally restrictive fashion. Palmitoylation is unique among lipid modifications in that it is readily reversible, controlled by the action of protein acyl transferases (DHHC PATs) and proposed acyl protein thioesterases (APTs). A model for Ras trafficking has been proposed that is based on cycles of acylation and deacylation coupled with membrane exchange (kinetic trap). The current proposal focuses on palmitoylation and depalmitoylation of yeast Ras proteins and determines how acylation/deacylation cycles control trafficking and signaling. Mutations in ras genes have been implicated in approximately 30% of all cancers, with the incidence Ras mutations appearing in some cancers being considerably higher. We have discovered that lipid modification of Ras proteins is required for Ras function and propose to study the role of lipid modification as a potential target of cancer chemotherapeutic drugs.

描述（由申请人提供）：RAS蛋白通过与包括RAF激酶，磷脂酰肌醇-3-激酶，RAL GEFS和Nore1的一系列效应子相互作用来调节多个细胞信号通路。这些调节相互作用的最佳特征是在质膜的细胞质表面上，响应于生长因子受体的信号。但是，现在显然，RAS还信号来自内膜室和质膜的不同微域。这对定义RAS和其他小单体GTPase的亚细胞靶向的机制提高了兴趣。我们专注于RAS蛋白的亚细胞靶向，以了解脂质修饰如何有助于蛋白质运输和信号传导。 RAS蛋白是通过CAAX盒原化（Farnesylation），-AAX裂解，甲基化以及K -Ras（K -RAS，棕榈酰化除外）在翻译后修饰的。亚细胞靶向需要翻译后修饰，但在空间和时间限制性的方式中也起着关键作用。棕榈酰化在脂质修饰之间是独一无二的，因为它很容易可逆，由蛋白酰基转移酶（DHHC PATS）和提出的酰基蛋白硫酯酶（APTS）控制。已经提出了一种基于酰化和脱酰化的循环与膜交换（Kinetic Trap）的循环的模型。当前的提案着重于酵母RAS蛋白的棕榈酰化和去山霉素化，并确定酰化/脱酰化周期如何控制运输和信号传导。 RAS基因中的突变已与所有癌症的大约30％有关，其中一些癌症中出现的RAS突变较高。我们已经发现，RAS功能需要对Ras蛋白进行脂质修饰，并建议研究脂质修饰作为癌症化学治疗药物的潜在靶标。