Regulation of cAMP production by tissue transglutaminase

组织转谷氨酰胺酶对 cAMP 产生的调节

• 批准号: 6953168
• 负责人: JANUSZ TUCHOLSKI
• 金额: $ 5.96万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953168
• 关键词: adenylate cyclase; amidation /deamidation; biological signal transduction; cAMP response element binding protein; cell line; cyclic AMP; enzyme activity; forskolin; gene expression; genetically modified animals; guanosinetriphosphatases; intracellular transport; laboratory mouse; neural plasticity; phosphodiesterases; protein glutamine gamma glutamyltransferase; protein protein interaction; protein structure function; protein transport; purinergic receptor; receptor expression; yeast two hybrid system

DESCRIPTION (provided by applicant): #7. Protein Modification: Tissue transglutaminase (tTG), an atypical member of the transglutaminase protein family, is a calcium-activated transamidating enzyme that modifies proteins by catalyzing the incorporation of polyamines, deamination or crosslinking. In addition, tTG binds and hydrolyzes GTP and has been proposed to act as a signal transducing G-protein. tTG is upregulated in several neurodegenerative diseases, including Alzheimer's disease, and it has been proposed that this is detrimental to cell survival because tTG can be pro-apoptotic. However, tTG can also be anti-apoptotic in neuronal cells depending on the stressor and further, we have clearly demonstrated that tTG can facilitate neurite outgrowth. These data demonstrate that tTG likely has multiple functions in the cell, and has the capacity to facilitate neuronal survival and function. Therefore, it can be proposed that the initial increase in tTG levels in neurodegenerative conditions may be a compensatory response and be beneficial to neuronal survival. We have recently found that tTG greatly enhances cAMP production resulting in phosphorylation and activation of the transcription factor cAMP-responsive element binding protein (CREB); an event that can support neuronal survival and plasticity. Further, we have demonstrated that the ability of tTG to facilitate cAMP production is dependent in part on its transamidating activity. These are very exciting findings, as they provide a possible mechanism by which tTG facilitate both neurite outgrowth and survival. Considering these and other data our overall hypothesis is that tTG directly modulates the activity of adenylyl cyclase, resulting in enhanced cAMP production and thus supports neuronal survival and plasticity. The specific aims of this application are to test the hypotheses that: (1) modulation of cAMP production by tTG requires both its transamidating and GTPase activity, and (2) tTG regulates cAMP production by interacting with and/or modifying specific components of the cAMP signaling pathway. The results of these studies will provide important new information on the function of tTG in neurons and provide the basis for an R01 application.

描述（由申请人提供）：#7。蛋白质修饰：组织转氨酶（tTG）是转氨酶蛋白家族的非典型成员，是一种钙激活的转酰胺酶，通过催化多胺的掺入、脱氨基或交联来修饰蛋白质。此外，tTG结合并水解GTP，并已被提出充当信号转导G蛋白。tTG在几种神经退行性疾病中上调，包括阿尔茨海默病，并且已经提出这对细胞存活是有害的，因为tTG可以是促凋亡的。然而，tTG也可以在神经元细胞中抗凋亡，这取决于应激源，并且进一步地，我们已经清楚地证明了tTG可以促进神经突生长。这些数据表明，tTG可能在细胞中具有多种功能，并且具有促进神经元存活和功能的能力。因此，可以提出，在神经退行性疾病中tTG水平的初始增加可能是一种代偿反应，并有利于神经元的存活。 我们最近发现，tTG大大提高cAMP的生产，导致磷酸化和激活的转录因子cAMP反应元件结合蛋白（CREB），一个事件，可以支持神经元的生存和可塑性。此外，我们已经证明tTG促进cAMP产生的能力部分取决于其转酰胺活性。这些是非常令人兴奋的发现，因为它们提供了一种可能的机制，tTG促进神经突生长和存活。考虑到这些和其他数据，我们的总体假设是tTG直接调节腺苷酸环化酶的活性，导致cAMP产生增强，从而支持神经元存活和可塑性。本申请的具体目的是检验以下假设：（1）tTG对cAMP产生的调节需要其转酰胺活性和GTT活性，以及（2）tTG通过与cAMP信号传导途径的特定组分相互作用和/或修饰cAMP信号传导途径的特定组分来调节cAMP产生。这些研究的结果将为tTG在神经元中的功能提供重要的新信息，并为R 01的应用提供基础。