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J. Cell Biol. 153 (1): 207-220

Copyright © 2001 by the Rockefeller University Press.


Original Article

Role of Diacylglycerol Kinase {alpha} in the Attenuation of Receptor Signaling

Miguel Angel Sanjuána, David R. Jonesa, Manuel Izquierdob, , and Isabel Méridaa

a Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, E-28049 Madrid, Spain
b Instituto de Biología y Genética Molecular, Facultad de Medicina, CSIC-Universidad de Valladolid, E-47005 Valladolid, Spain
Dept. of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientifícas, Cantoblanco, E-28049 Madrid, Spain.34-91-372-049334-91-585-4665

imerida{at}cnb.uam.es

Abstract: 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{alpha}, 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{alpha}-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{alpha} exerts on diacylglycerol-derived cell responses. This study is the first to describe DGK{alpha} 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



Abbreviations used in this paper: BAPTA, 1,2-bis(aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; DGK, DAG kinase; DiC8, 1,2-dioctanoyl sn-glycerol; GFP, green fluorescent protein; IL, interleukin; PA, phosphatidic acid; PBut, phosphatidylbutanol; PDBu, 1,2-dioleoylglycerol, phorbol-12,13-dibutyrate; PE, phycoerythrin; PI4,5P2, phosphatidylinositol 4,5-bisphosphate; PLD, phospholipase D; SAX-HPLC, strong ion exchange high performance liquid chromatography; TCR, T cell receptor.


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