Spatial control of cAMP signaling by Epacs

Epacs 对 cAMP 信号传导的空间控制

• 批准号: 8502657
• 负责人: PHILIP J.S. STORK
• 金额: $ 26.01万
• 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/8502657
• 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）：该提案检查了一类新型 cAMP 调节蛋白（由 cAMP 激活的交换蛋白（Epacs））的生理功能，并测试了每种亚型（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 本身之外 cAMP 的主要细胞内靶标。我们对小 G 蛋白 Rap1 的 Epac 激活的研究表明，交换子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 等人，2006 年；Liu 等人，2008 年）。我们在 Epac 1 和 Epac2 中识别出不同的靶向域，称为 Ras 关联 (RA) 域（Liu et al. 2008）。我们认为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 Rap1 的不同亚细胞池。我们认为 Epac1 和 Epac2 的 RA 结构域分别将 cAMP 信号传导与小 G 蛋白 Ran 和 Ras 连接起来。这可以解释 Ran 如何耦合到 Rap1（通过 Epac1 交换器）以及 Ras 如何耦合到 Rap1（通过 Epac2 交换器）。本提案检查了该模型及其对 Epac1 和 Epac2 的生理影响。我们发现 Epac1 在核孔处与小 G 蛋白 Ran 结合。我们将测试以下假设：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。这代表了 Ran 与细胞内信号级联的第一个链接，并确定了 Epac1 和 Rap 的新功能。这一发现的意义在于，通过 Ran 循环进行的蛋白质核易位控制着细胞生长和分化，其失调是许多癌症的标志。我们证明 Epac1 调节癌蛋白 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 相比，我们认为 Epac2 与质膜上激活的 Ras 结合，将 cAMP 和 Ras 与 Rap1 激活联系起来。 Epac2 模型作为 Ras 和 cAMP 信号的重合检测器，对糖尿病具有重要意义，因为现在已知 Epac 是磺酰脲类药物的靶标。我们在这里首次提出 Ras 和 cAMP 信号在 Epac2 上汇聚以增强胰岛素释放的模型。如果属实，这将建立一种治疗糖尿病的创新方法，包括将 Ras 激活剂与模拟胰岛素激素和磺酰脲类药物相结合。