Regulation of T Cell Receptor-induced Activation of the Ras-ERK Pathway by Diacylglycerol Kinase ζ*

By X. Zhong, Ehmonie A. Hainey, B. Olenchock, Haoran Zhao, M. Topham, G. Koretzky. Journal of Biological Chemistry, 2002

109 citations recorded by the source corpus.

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 θ. Because both RasGRP and protein kinase C θ 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 ζ (DGKζ, 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 DGKζ 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 DGKζ, are required for its inhibitory effects. Collectively these studies demonstrate a potential role of DGKζ 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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4fbef818dc7fadb3066cd9adf3031d9a78a44b21

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Citations in the corpus

• Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy (2012, background): “T cell receptor (TCR) signaling and, consequently, resulted in the anergy of T cells [62,63].”