Role of membranes in modulating the activity of diacylglycerol kinases

膜在调节二酰甘油激酶活性中的作用

• 批准号: 576144-2022
• 负责人: Epand, RichardRM
• 金额: $ 1.82万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744154
• 关键词: Role; membranes; modulating; activity; diacylglycerol

We will study a family of enzymes, the diacylglycerol kinases (DGKs) important for regulating a number of biological processes. Among the processes that DGK regulates is cell proliferation, including cancer cells. In addition, DGK regulates the immune response of T-cells. The long-term goal is to understand the role of membranes in modulating the activity of DGKs. This work is important for immunological surveillance and is required to inhibit the proliferation of cancer cells. Recent work has revealed the possibility that DGKz together with the enzyme sphingomyelin synthase related protein (SmSrP) could form a cycle in which the concentrations of the signaling agents diacylglycerol (DAG) and phosphatidic acid (PA) remain constant over time if there is sufficient ATP and as long as both DGKz and SmSrP act on lipid substrates with the same "tails". This would be a conceptually new role for a DGK. Until now it has been often stated that DGKs are unique in signal transduction in that they convert one signaling modulator, DAG, to another, PA, thus simultaneously turning off and on a whole group of different proteins. This would make DGKz together with SmSrP different, in that they would maintain the levels of DAG and PA constant for a period of time. As a consequence, inhibitors of DGKz, that are currently being actively developed for cancer therapy, would not be effective in affecting DAG or PA levels as long as this cycle was operative. However, we have shown that membrane shape affects the specificity of DGK. Hence, membrane shape or cell morphology may control which of the two motifs of regulation are employed, i.e. converting DAG to PA or maintaining DAG and PA constant over time. This knowledge will be required to understand the action of a pharmacological agent designed to affect the activity of DGKz. Such agents may be effective DGK inhibitors only in certain circumstances. To increase the likelihood of efficacy, clinical trials with inhibitors of DGKz should be undertaken only when conditions that limit the recycling are met. These conditions can be established in the laboratory with preclinical trials that measure the conditions required for the coupling of DGKz and SmSrP.

我们将研究一个家族的酶，二酰基甘油激酶（DGKs）的重要调控的一些生物过程。DGK调节的过程之一是细胞增殖，包括癌细胞。此外，DGK调节T细胞的免疫应答。长期目标是了解膜在调节DGKs活性中的作用。这项工作对于免疫监视是重要的，并且是抑制癌细胞增殖所必需的。最近的工作已经揭示了DGKz与鞘磷脂合成酶相关蛋白（SmSrP）一起可以形成一个循环的可能性，其中如果有足够的ATP并且只要DGKz和SmSrP都作用于具有相同“尾部”的脂质底物，则信号传导剂二酰基甘油（DAG）和磷脂酸（PA）的浓度随时间保持恒定。这将是一个概念上的新作用，为总干事。到目前为止，人们经常说DGK在信号转导中是独特的，因为它们将一种信号调节剂DAG转化为另一种信号调节剂PA，从而同时关闭和打开一整组不同的蛋白质。这将使DGKz与SmSrP不同，因为它们将在一段时间内保持DAG和PA的水平恒定。因此，只要这个周期有效，目前正在积极开发用于癌症治疗的DGKz抑制剂就不会有效影响DAG或PA水平。然而，我们已经表明，膜形状影响DGK的特异性。因此，膜形状或细胞形态可以控制采用两种调控基序中的哪一种，即将DAG转化为PA或随时间保持DAG和PA恒定。这方面的知识将需要了解的作用，药物的设计，以影响DGKz的活动。此类药剂仅在某些情况下可以是有效的DGK抑制剂。为了增加疗效的可能性，只有在满足限制再循环的条件时，才应进行DGKz抑制剂的临床试验。这些条件可以通过临床前试验在实验室中建立，这些临床前试验测量DGKz和SmSrP偶联所需的条件。