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Review
. 2013 Mar 26;14(4):6649-73.
doi: 10.3390/ijms14046649.

Diacylglycerol kinases: regulated controllers of T cell activation, function, and development

Rohan P Joshi  1 , Gary A Koretzky
Affiliations
Review

Diacylglycerol kinases: regulated controllers of T cell activation, function, and development

Rohan P Joshi et al. Int J Mol Sci. .

Abstract

Diacylglycerol kinases (DGKs) are a diverse family of enzymes that catalyze the conversion of diacylglycerol (DAG), a crucial second messenger of receptor-mediated signaling, to phosphatidic acid (PA). Both DAG and PA are bioactive molecules that regulate a wide set of intracellular signaling proteins involved in innate and adaptive immunity. Clear evidence points to a critical role for DGKs in modulating T cell activation, function, and development. More recently, studies have elucidated factors that control DGK function, suggesting an added complexity to how DGKs act during signaling. This review summarizes the available knowledge of the function and regulation of DGK isoforms in signal transduction with a particular focus on T lymphocytes.

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Figures

Figure 1
Figure 1
Diacylglycerol kinases (DGK) isoforms are divided into five subtypes based on domains apart from the C1 and catalytic domains. RVH: recoverin homology domain. PH: pleckstrin homology domain. SAM: sterile α motif. M: MARCKS homology domain. ANK, ankyrin repeat domain; PDZ-bind, PDZ-binding domain; Note, domain sizes are not to scale.
Figure 2
Figure 2
Diacylglycerol has a central role in TCR signaling. Engagement of the TCR leads to the activation of tyrosine kinases and the formation of a multimolecular complex including adapter proteins. PLCγ1 is recruited to and activated by this complex and in turn hydrolyses the phospholipid PIP2 to form membrane-diffusible diacylglycerol (DAG) and cytosolic IP3. DAG activates proteins including RasGRP1, PKCs, and PKD. Activation of RasGRP1 leads to Ras and AKT pathway activation. Activation of PKCs leads to the activation of NF-κB and cytoskeletal repolarization. Activation of PKD leads to integrin activation. IP3, Ras, and PKC-θ signaling cooperate to promote T cell activation through the transcription factors NFAT, AP-1, and NF-κB, respectively. Diacylglycerol kinases (DGKs) phosphorylate DAG to form phosphatidic acid (PA), thereby potentially regulating a broad set of signaling pathways downstream of the TCR.
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