Nuclear Signaling Complexes

核信号复合物

• 批准号: 6889209
• 负责人: VINCENT M COGHLAN
• 金额: $ 23.41万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889209
• 关键词: A kinase anchoring protein; SDS polyacrylamide gel electrophoresis; binding sites; biological signal transduction; cell nucleus; confocal scanning microscopy; gene expression; genetic transcription; immunocytochemistry; immunoprecipitation; nuclear matrix; protein kinase A; protein structure function; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): An emerging theme in cellular organization is that for many metabolic pathways, cells utilize large, multi-enzyme complexes that are recruited to specific subcellular sites through protein-protein interactions. Complex formation may play an important role in cellular signal transduction pathways as a means to target the activities of signaling enzymes and ensure an appropriate cellular response to a given stimulus. Many signaling cascades ultimately converge in the cell nucleus and the objective of this project is to characterize proteins that recruit signaling enzymes at the nuclear matrix. Using in-vitro approaches and experiments with cultured cells, we will investigate the cellular function of AKAP95, a novel anchoring protein for the cAMP-dependent protein kinase (PKA) that localizes to the nuclear matrix. The specific aims of this proposal will test the hypothesis that AKAP95 plays a critical role in recruiting PKA to initiation complexes involved in hormone-induced gene expression. We will also investigate nuclear anchoring of other signaling enzymes by NAKAP95. a newly discovered protein that is related to AKAP95 but does not bind PKA. Using novel inhibitor peptides and expression systems, we will determine the functional effect of disrupting anchoring protein-mediated targeting on the transcription of specific genes. These studies have particular relevance to cancer, as malignant progression is accompanied by changes in nuclear organization, gene expression, and the control of cellular signaling pathways.

描述（由申请人提供）：细胞组织中的一个新兴主题是，对于许多代谢途径，细胞利用大型多酶复合物通过蛋白质 - 蛋白质相互作用募集到特定的亚细胞位点。复合物的形成可能在细胞信号转导途径中起重要作用，作为靶向信号酶活性并确保对给定刺激的适当细胞反应的一种手段。许多信号级联对于细胞核中最终汇聚，该项目的目的是表征蛋白质，这些蛋白质在核基质处募集信号传导酶。使用培养细胞的体外方法和实验，我们将研究AKAP95的细胞功能，AKAP95是一种依赖CAMP依赖性蛋白激酶（PKA）的新型锚定蛋白，该蛋白质定位于核基质。该提案的具体目的将检验以下假设：AKAP95在将PKA招募到参与激素诱导的基因表达的起始复合物中起关键作用。我们还将通过NAKAP95研究其他信号酶的核锚定。与AKAP95相关但不结合PKA的新发现的蛋白质。使用新型抑制剂肽和表达系统，我们将确定破坏锚定蛋白介导的靶向对特定基因转录的功能效果。这些研究与癌症特别相关，因为恶性进展伴随着核组织，基因表达和细胞信号传导途径的控制。