Spatial control of cAMP signaling by Epacs

Epacs 对 cAMP 信号传导的空间控制

• 批准号: 8320237
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320237
• 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）：该提案研究了新型cAMP调节蛋白的生理功能，由CAMP激活（EPAC）激活的交换蛋白质，并检验了新型假设，即每个同工型（EPAC1和ERPAC2）都能在细胞中携带不同的生理功能。这个蛋白质家族直接结合营地，并代表了PKA本身以外的其他营地的主要细胞内靶标。我们对小G蛋白RAP1激活EPAC激活的研究表明，交换器的亚细胞定位可以决定其激活的G蛋白使用的效应子的选择（Wang等，2006; Liu etal。2008）。我们已经确定了EPAC 1和EPAC2中的不同靶向域称为RAS关联（RA）域（Liu等，2008）。我们建议这些结构域允许特定的小G蛋白分别与EPAC1和EPAC2连接到RAP1的不同亚细胞池的激活。我们提出，EPAC1和EPAC2的RA结构域分别连接到小G蛋白，RAN和RAS。这可以解释夫妻如何与RAP1（通过EPAC1交换器）以及RAS如何搭配到RAP1（通过EPAC2交换器）。在此提案中检查了该模型及其对EPAC1和EPAC2的生理后果。我们已经发现EPAC1与小G蛋白在核孔中结合。我们将检验以下假设：EPAC1夫妇的RA结构域将gtp延伸至RAP1以调节蛋白质的转运和从细胞核中传递。这代表了运行到细胞内信号级联的第一个链接，并确定了EPAC1和RAP的新功能。这一发现的重要性是，通过RAN循环的蛋白质核易位控制细胞的生长和分化，其失调是许多癌症的标志。我们表明，EPAC1调节癌蛋白2-catenin的核功能。我们建议EPAC1的这一功能可以解释CAMP的某些抗增殖作用。与EPAC1相反，我们提出EPAC2与质膜上激活的RAS结合，将CAMP和RAS与RAP1激活联系起来。 EPAC2的这种模型作为通过RAS和CAMP的信号的巧合检测器对糖尿病具有重要意义，因为现在已知EPAC是磺酰氟烷的靶标。我们在这里首次提出了RAS和CAMP信号在EPAC2上汇聚以增强胰岛素释放的模型。如果是真的，这将建立一种创新的糖尿病方法，涉及将RAS活化剂与胰岛素瘤激素和磺酰脲药物相结合的糖尿病。