Original Article

Role of Diacylglycerol Kinase in the Attenuation of Receptor Signaling

Correspondence to: Isabel Mérida, Dept. of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientifícas, Cantoblanco, E-28049 Madrid, Spain. Tel:34-91-585-4665 Fax:34-91-372-0493 E-mail:imerida{at}cnb.uam.es.

Diacylglycerol kinase (DGK) is suggested to attenuate diacylglycerol-induced cell responses through the phosphorylation of this second messenger to phosphatidic acid. Here, we show that DGK, an isoform highly expressed in T lymphocytes, translocates from cytosol to the plasma membrane in response to two different receptors known to elicit T cell activation responses: an ectopically expressed muscarinic type I receptor and the endogenous T cell receptor. Translocation in response to receptor stimulation is rapid, transient, and requires calcium and tyrosine kinase activation. DGK-mediated phosphatidic acid generation allows dissociation of the enzyme from the plasma membrane and return to the cytosol, as demonstrated using a pharmacological inhibitor and a catalytically inactive version of the enzyme. The NH₂-terminal domain of the protein is shown to be responsible for receptor-induced translocation and phosphatidic acid–mediated membrane dissociation. After examining induction of the T cell activation marker CD69 in cells expressing a constitutively active form of the enzyme, we present evidence of the negative regulation that DGK exerts on diacylglycerol-derived cell responses. This study is the first to describe DGK as an integral component of the signaling cascades that link plasma membrane receptors to nuclear responses.

Key Words: diacylglycerol kinase, lymphocytes, T cell activation, signal transduction, green fluorescent protein

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