Role of membranes in modulating the activity of diacylglycerol kinases

我们将研究一个酶家族，二酰基甘油激酶（DGKs）对调节许多生物过程很重要。DGK调节的过程之一是细胞增殖，包括癌细胞。此外，DGK还调节t细胞的免疫反应。长期目标是了解细胞膜在调节DGKs活性中的作用。这项工作对免疫监测和抑制癌细胞增殖是很重要的。最近的研究表明，DGKz与鞘磷脂合成酶相关蛋白（SmSrP）可能形成一个循环，在这个循环中，如果有足够的ATP，只要DGKz和SmSrP以相同的“尾巴”作用于脂质底物，那么信号剂二酰基甘油（DAG）和磷脂酸（PA）的浓度随时间保持不变。这将是DGK在概念上的新角色。到目前为止，人们通常认为dgk在信号转导中是独特的，因为它们将一种信号调节剂DAG转换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，因为它们会在一段时间内维持DAG和PA的水平不变。因此，目前正在积极开发用于癌症治疗的DGKz抑制剂，只要这个周期有效，就不会有效影响DAG或PA水平。然而，我们已经证明膜形状影响DGK的特异性。因此，膜的形状或细胞的形态可以控制两种调控基序中的哪一种被使用，即将DAG转化为PA或保持DAG和PA随时间的不变。这方面的知识将需要理解药理学制剂的作用，旨在影响DGKz的活性。这些药物仅在某些情况下可能是有效的DGK抑制剂。为了提高疗效的可能性，DGKz抑制剂的临床试验应仅在满足限制回收的条件时进行。这些条件可以在实验室通过临床前试验确定，测量DGKz和SmSrP偶联所需的条件。

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.