Spatial control of cAMP signaling by Epacs

Epacs 对 cAMP 信号传导的空间控制

• 批准号: 8685251
• 负责人: PHILIP J.S. STORK
• 金额: $ 26.95万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685251
• 关键词: Affect; Agonist; Alzheimer' s Disease; Binding; Biological; Carrier Proteins; Cell Adhesion; Cell Differentiation process; Cell Nucleus; Cell membrane; Cell physiology; Cells; Couples; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Diabetes Mellitus; Family; GTP-Binding Proteins; Genetic Transcription; Growth Factor; Guanine Nucleotides; Guanosine Triphosphate; Hormonal; Hormones; Insulin; Link; Locales; Malignant Neoplasms; Mammalian Cell; Mediating; Modeling; Molecular; Monomeric GTP-Binding Proteins; Normal Cell; Nuclear; Nuclear Envelope; Nuclear Pore; Nuclear Pore Complex; Nuclear Proteins; Nuclear Translocation; Oncogene Proteins; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Protein Isoforms; Proteins; Recruitment Activity; Regulation; Role; Running; Signal Pathway; Signal Transduction; Site; Sulfonylurea Compounds; Synaptic plasticity; Testing; Therapeutic; Time; adenosine cyclic-3' ,5' -monophosphate binding proteins; base; cancer cell; carcinogenesis; cell growth; cellular development; design; detector; diabetic patient; innovation; insulin secretion; member; novel; nucleocytoplasmic transport; response; therapeutic target; trafficking; transcription factor

DESCRIPTION (provided by applicant): This proposal examines the physiological function of a novel class of cAMP-regulated proteins, the exchange proteins activated by cAMP (Epacs) and tests the novel hypothesis that each isoform (Epac1 and ERpac2) carries out distinct physiological functions in the cell. This family of proteins binds cAMP directly and represents the major intracellular target of cAMP other than PKA itself. Our studies of Epac activation of small G protein Rap1 have demonstrated that subcellular localization of exchangers can dictate the choice of effectors utilized by the G proteins they activate (Wang et al. 2006; Liu et al. 2008). We have identified distinct targeting domains in both Epac 1 and Epac2 called Ras association (RA) domains (Liu et al. 2008). We propose that these domains allow specific small G proteins to link to Epac1 and Epac2, respectively, to the activation of distinct subcellular pools of Rap1. We propose that the RA domains of Epac1 and Epac2 link cAMP signaling to the small G proteins, Ran and Ras, respectively. This can explain how Ran couples to Rap1 (via the Epac1 exchanger) and how Ras can couple to Rap1 (via the Epac2 exchanger). This model and its physiological consequences for both Epac1 and Epac2 are examined in this proposal. We have discovered that Epac1 binds to the small G protein Ran at the nuclear pore. We will test the hypothesis that the RA domain of Epac1 couples Ran-GTP to Rap1 to regulate the transport of proteins in and out of the nucleus. This represents the first link of Ran to intracellular signaling cascades and identifies a novel function for both Epac1 and Rap. The significance of this finding is that the nuclear translocation of proteins via the Ran cycle governs cell growth and differentiation, and its dysregulation is a hallmark of many cancers. We show that Epac1 regulates the nuclear functions of the oncoprotein 2-catenin. We propose that this and related functions of Epac1 may explain some of the anti-proliferative effects of cAMP. In contrast to Epac1, we propose that Epac2 binds to activated Ras at the plasma membrane to link cAMP and Ras to Rap1 activation. This model of Epac2 function as a coincidence detector for signals through Ras and cAMP has significant implications for diabetes, as Epacs are now known to be targets of the sulfonylureas. We propose here for the first time a model that Ras and cAMP signals converge on Epac2 to potentiate insulin release. If true, this would establish an innovative approach to diabetes involving combining Ras activators with both insulinomimetic hormones and the sulfonylurea drugs.

描述（由申请人提供）：本提案研究了一类新的cAMP调节蛋白的生理功能，即cAMP激活的交换蛋白（Epacs），并验证了每个异构体（Epac1和ERpac2）在细胞中执行不同生理功能的新假设。该蛋白家族直接结合cAMP，是除PKA外cAMP的主要细胞内靶点。我们对Epac激活小G蛋白Rap1的研究表明，交换器的亚细胞定位可以决定它们激活的G蛋白所利用的效应器的选择（Wang et al. 2006; Liu et al. 2008）。我们已经在epac1和Epac2中发现了不同的靶向结构域，称为Ras关联（RA）结构域（Liu et al. 2008）。我们提出这些结构域允许特定的小G蛋白分别连接到Epac1和Epac2，从而激活不同的Rap1亚细胞池。我们认为Epac1和Epac2的RA结构域分别将cAMP信号连接到小G蛋白Ran和Ras。这可以解释Ran如何与Rap1配对（通过Epac1交换器）以及Ras如何与Rap1配对（通过Epac2交换器）。本研究对该模型及其对Epac1和Epac2的生理影响进行了研究。我们发现Epac1在核孔处与小G蛋白Ran结合。我们将验证Epac1的RA结构域将Ran-GTP与Rap1偶联以调节蛋白质进出细胞核的运输的假设。这代表了Ran与细胞内信号级联的第一个联系，并确定了Epac1和Rap的新功能。这一发现的意义在于，通过Ran循环的蛋白质核易位控制着细胞的生长和分化，其失调是许多癌症的标志。我们发现Epac1调控癌蛋白2-连环蛋白的核功能。我们认为Epac1的这一功能和相关功能可以解释cAMP的一些抗增殖作用。与Epac1相反，我们提出Epac2在质膜上与活化的Ras结合，将cAMP和Ras与Rap1激活联系起来。这种Epac2模型作为Ras和cAMP信号的一致性检测器，对糖尿病具有重要意义，因为Epacs现在已知是磺脲类药物的靶标。我们首次提出Ras和cAMP信号在Epac2上汇聚从而增强胰岛素释放的模型。如果这是真的，这将建立一种将Ras激活剂与拟胰岛素激素和磺脲类药物联合使用的治疗糖尿病的创新方法。