Regulation of heterotrimeric G proteins by non-receptor activators

非受体激活剂对异源三聚体 G 蛋白的调节

• 批准号: 8136505
• 负责人: Gregory Gordon Tall
• 金额: $ 31.42万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136505
• 关键词: Ablation; Adenylate Cyclase; Affinity Chromatography; Attenuated; Binding; Binding Proteins; Biochemical; Biology; Caenorhabditis elegans; Catalysis; Catalytic Domain; Cell Line; Cell division; Cell membrane; Cell surface; Cells; Complement; Cytosol; Defect; Development; Drosophila genus; ES Cell Line; Engineering; Enzymes; Esthesia; Event; Fractionation; Future; G alpha q Protein; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gene Expression; Genetic; Goals; Guanine Nucleotide Exchange Factors; Guanine Nucleotides; Guanosine Triphosphate; Harvest; Heterotrimeric GTP-Binding Proteins; Histones; Homologous Gene; Hormones; Human; Human G(i) Alpha Proteins; Hydrolysis; In Vitro; Intervention; Knock-out; Knowledge; Malignant Neoplasms; Mammalian Cell; Mammals; Mechanics; Mediating; Membrane; Mitosis; Modeling; Mus; Normal Cell; Output; Pathway interactions; Pharmacologic Substance; Phospholipase; Physiological; Physiology; Process; Property; Protein Subunits; Proteins; RNA Interference; RNA Splicing; Reagent; Regulation; Reporter; Research; Role; Sensory; Signal Transduction; Smell Perception; Specificity; Staging; Stem cells; Techniques; Technology; Testing; Therapeutic; Therapeutic Uses; Tissues; Tubulin; Variant; Work; Wound Healing; adult stem cell; base; blastocyst; catalyst; design; embryonic stem cell; gastrulation; hormone regulation; in vivo; neurotransmission; novel; prospective; protein activation; protein expression; protein transport; prototype; public health relevance; repaired; research study; stem cell division; trafficking

DESCRIPTION (provided by applicant): Heterotrimeric G proteins are eminent signal transducing molecules that facilitate human sensation and hormone-regulation of physiology. Traditional G protein signaling pathways are activated by the action of G protein coupled receptors (GPCRs) present on the surface of cells. Recently, new mechanisms of heterotrimeric G protein regulation have been appreciated. Enzymes that are not GPCRs activate G proteins by non-traditional means and regulate pathways not previously attributed to G protein control. Prototypes of these new G protein activators are the Ric-8 proteins. The mammalian Ric-8A homolog activates G protein alpha subunits by stimulating catalysis of GDP for GTP exchange. Ric-8 proteins likely modulate G protein signaling regulation of asymmetric (adult stem cell) and normal cell division (G protein alpha i), aspects of neurotransmission (G protein alpha q), and olfaction (G protein alpha olf). Perhaps underlying this seeming regulation of divergent G protein signaling pathways is the finding that Drosophila RIC-8 appears to be required for the proper expression and plasma membrane localization of heterotrimeric G proteins. The goal of this proposal is to understand in detail, the unique regulation of G protein physiology by both mammalian Ric-8 homologs (A and B). The aims of the proposal are to: (1) examine the hypothesis that Ric-8B proteins activate G protein alpha s subunits by serving as guanine nucleotide exchange catalysts, (2) test the hypothesis in mammals, that Ric-8 proteins are required globally for G protein localization at the cell plasma membrane. (3) test the hypothesis that the mammalian Ric-8A homolog is responsible for activating G protein alpha i- dependent (asymmetric) cell division (4) define the authentic cellular interactions between the compendium of G protein subunits and Ric-8A or Ric-8B. The technology developed to define these interactions will also be used to uncover novel interactions between Ric-8 proteins and other proteins in addition to G proteins. Ric-8 proteins are new G protein activators. Many pharmaceuticals intervene to alter the process of GPCR-mediated G protein activation. Elucidation of the novel mechanisms by which Ric-8 proteins regulate G proteins may enable the engineering of new classes of therapeutics that intervene at the level of Ric-8 activation of G proteins. Furthermore, contributing basic knowledge towards understanding the mechanism(s) by which Ric-8 and G proteins control normal and defective stem cell division could profit: (1) the therapeutic use of stem cells to repair damaged tissues and (2) treatment of stem cell derived cancers. PUBLIC HEALTH RELEVANCE: Heterotrimeric G protein activation is a primary target of pharmaceutical intervention. Defining the unique mechanisms by which Ric-8 proteins activate G proteins will enable the design of new classes of therapeutics that alter the consequences of G protein activation. This research will also define Ric-8 control of G protein-directed stem cell division and contribute efforts to use stem cells for tissue repair and the eradication of cancers derived from defectively dividing stem cells.

描述（由申请人提供）：异三聚体G蛋白是促进生理学的人类感觉和激素调节的显着信号转导的分子。传统的G蛋白信号通路通过存在于细胞表面上的G蛋白偶联受体（GPCR）的作用激活。最近，已理解异三聚体G蛋白调节的新机制。不是GPCR的酶通过非传统手段激活G蛋白，并调节以前不归因于G蛋白控制的途径。这些新G蛋白激活剂的原型是RIC-8蛋白。哺乳动物RIC-8A同源物通过刺激GDP的GDP交换来激活G蛋白α亚基。 RIC-8蛋白可能调节G蛋白信号传导调节不对称（成人干细胞）和正常细胞分裂（G蛋白αI），神经传递的方面（G蛋白αQ）和嗅觉（G蛋白αOLF）。也许是基本的这种不同G蛋白信号传导途径的调控是，果蝇RIC-8似乎是正确表达和质膜定位的果蝇RIC-8。该提案的目的是详细了解，这是哺乳动物RIC-8同源物（A和B）对G蛋白质生理的独特调节。该提案的目的是：（1）检查RIC-8B蛋白通过用作鸟嘌呤核苷酸交换催化剂来激活G蛋白α的亚基的假设，（2）测试哺乳动物中的假设，即RIC-8蛋白需要在细胞质膜上的G蛋白质局限于全球ric-8蛋白。 （3）检验了哺乳动物RIC-8A同源物负责激活G蛋白αI-依赖性（非对称）细胞分裂的假设（4）定义了G蛋白亚基和RIC-8A或RIC-8A或RIC-8B之间的真实细胞相互作用。为定义这些相互作用而开发的技术还将用于发现除G蛋白外，除了G蛋白外，RIC-8蛋白与其他蛋白质之间的新相互作用。 RIC-8蛋白是新的G蛋白活化剂。许多药物干预以改变GPCR介导的G蛋白激活的过程。阐明RIC-8蛋白调节G蛋白的新机制可以使新的疗法的工程在RIC-8激活G蛋白的激活水平上进行干预。此外，有助于理解RIC-8和G蛋白控制正常和有缺陷的干细胞分裂的机制可以利润的机制：（1）使用干细胞修复受损组织的治疗以及（2）处理干细胞衍生的癌症。 公共卫生相关性：异三聚体G蛋白激活是药物干预的主要目标。定义RIC-8蛋白激活G蛋白的独特机制将实现新的治疗剂的设计，从而改变G蛋白激活的后果。这项研究还将定义RIC-8对G蛋白指导的干细胞分裂的控制，并为使用干细胞进行组织修复和消除源自缺陷的干细胞的癌症做出努力。