Role of membranes in modulating the activity of diacylglycerol kinases

我们将研究一类酶，二酰甘油激酶(DGKs)，它对调节许多生物过程很重要。DGK调控的过程包括细胞增殖，包括癌细胞。此外，DGK还调节T细胞的免疫反应。长期目标是了解膜在调节DGKs活性中的作用。这项工作对免疫学监测很重要，并需要抑制癌细胞的增殖。最近的工作揭示了DGKz与鞘磷脂合成酶相关蛋白(SmSrP)一起形成一个循环的可能性，在这个循环中，如果有足够的ATP，只要DGKz和SmSrP都作用于具有相同尾巴的脂质底物，信号试剂二酰甘油(DAG)和磷脂酸(PA)的浓度随着时间的推移保持不变。对于DGK来说，这将是一个概念上的新角色。到目前为止，人们经常说DGK在信号转导中是独一无二的，因为它们将一个信号调节器DAG转换为另一个信号调节器PA，从而同时关闭和开启一整组不同的蛋白质。这将使DGKz和SmSrP有所不同，因为它们将在一段时间内保持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，只要这个周期仍然有效，就不会有效地影响DAG或PA水平。然而，我们已经证明，膜的形状影响DGK的特异性。因此，膜形状或细胞形态可能控制两个调控基序中的哪一个，即将DAG转换为PA或随着时间的推移保持DAG和PA恒定。要了解旨在影响DGKz活性的药理剂的作用，需要了解这些知识。此类药物只有在某些情况下才可能是有效的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。这些条件可以在实验室通过临床前试验来确定，这些试验测量了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.