Role of membranes in modulating the activity of diacylglycerol kinases

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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.