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Originally published In Press as doi:10.1074/jbc.M203818200 on June 17, 2002

J. Biol. Chem., Vol. 277, Issue 34, 31089-31098, August 23, 2002
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Regulation of T Cell Receptor-induced Activation of the Ras-ERK Pathway by Diacylglycerol Kinase zeta *

Xiao-Ping ZhongDagger §, Ehmonie A. HaineyDagger ||, Benjamin A. Olenchock**, Haoran ZhaoDagger Dagger , Matthew K. Topham§§, and Gary A. KoretzkyDagger ||¶¶

From the Dagger  Signal Transduction Program, The Abramson Family Cancer Research Institute, the § Department of Cancer Biology, and the || Department of Pathology and Laboratory Medicine, the ** Immunology Graduate Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Dagger Dagger  Rigel Inc., South San Francisco, California 94080, and §§ The Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112

T cell development in the thymus and activation of mature T cells in the periphery depend on signals stimulated by engagement of the T cell antigen receptor (TCR). Among the second messenger cascades initiated by TCR ligation include the phosphatidylinositol pathway where the membrane phospholipid, phosphatidylinositol 4,5-bisphosphate, is hydrolyzed to inositol 1,4,5-trisphosphate and diacylglycerol (DAG). Inositol 1,4,5-trisphosphate signals a rise in intracellular free calcium, leading to translocation of nuclear factor of activated T cells into the nucleus. DAG activates RasGRP and protein kinase C theta . Because both RasGRP and protein kinase C theta  are essential for thymocyte and T cell function, it is critical to understand how DAG is regulated. In this report, we demonstrate expression of DAG kinase zeta  (DGKzeta , the enzyme that catalyzes the conversion of DAG to phosphatidic acid) in multiple lymphoid organs, with highest expression observed within the T cell compartment. Overexpression studies in Jurkat T cells indicate that DGKzeta interferes with TCR-induced Ras and ERK activation, AP-1 induction, and expression of the activation marker CD69. In contrast, TCR-stimulated calcium influx is not altered. Mutational analysis indicates that the kinase and DAG binding domains, but not the ankyrin repeats of DGKzeta , are required for its inhibitory effects. Collectively these studies demonstrate a potential role of DGKzeta to function as a selective negative regulator of DAG signaling on T cell activation and provide the first structure/function analysis of this enzyme in T cells.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a fellowship from the Cancer Research Institute, New York.

¶¶ To whom correspondence should be addressed: 415 BRBII/III, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-746-5522; Fax: 215-746-5525, E-mail: koretzky@mail.med.upenn.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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