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

Abstract

. In peripheral lymphoid organs, engagement of the TCR by antigenic peptide presented by major histocompatibility complex molecules on antigen presenting cells initiates a signaling cascade that is required for T cell proliferation and effector function (1, 5). Abnormalities in signals delivered by the TCR may result in either hypo-or hyperactivation leading to undesirable outcomes such as immune deficiency (6 -9) or autoimmunity (10 -12). Engagement of the TCR initiates numerous second messenger cascades. The most proximal known biochemical signal is stimulation of protein tyrosine kinases with subsequent tyrosine phosphorylation of multiple substrates (5,13,14). Among these substrates are phospholipase C␥1 (PLC␥1) (15-17) and critical adapters including linker of activated T cells (18) and SLP-76 (SH2 domain containing leukocyte phosphoprotein of 76 kDa) (19). These proteins in association with another adapter protein, Grb2-related adapter molecule downstream of , are part of a larger multimolecular complex required for PLC␥1 to act efficiently on its substrate (23-28). Activated PLC␥1 hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate two second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (29). Inositol 1,4,5-trisphosphate induces an influx of Ca 2ϩ that activates the calcineurinnuclear factor of activated T cells (NFAT) signaling pathway (30). DAG allosterically activates both RasGRP (31, 32), a nucleotide exchange factor for Ras, and PKC (33), a serine (threonine) kinase, through associating with the C1 domains of both molecules. Activated RasGRP (34, 35) and PKC (36, 37) in turn stimulate the Ras-ERK-AP-1 and NFB pathways, respectively. Propagation of these signaling cascades promotes the transcription of numerous genes including those encoding cytokines critical for T cell development, activation, and proliferation. Deficiencies of RasGRP (35) and PKC (37) cause defects in positive selection in developing thymocytes and inefficient activation of peripheral T cells. Similarly, PLC␥1 deficiency (with consequent defects in phosphatidylinositol 4,5-bisphosphate-derived second messenger production) abrogates TCR-mediated cellular activation in the Jurkat T cell

T Cell Activation In Vivo Targets Diacylglycerol Kinase α to the Membrane: A Novel Mechanism for Ras Attenuation

“…Very recently, overexpression of DGK , a type IV DGK, in Jurkat cells has been reported to regulate DAG-dependent responses such as CD69 expression or Ras activation (24). In contrast to DGK␣, for which only constitutive active and/or dominant-negative enzyme forms modulate TCR responses, wild-type DGK overexpression is sufficient to modulate these signals.…”

Defective Activation of Protein Kinase C and Ras-ERK Pathways Limits IL-2 Production and Proliferation by CD4+CD25+ Regulatory T Cells

“…It allosterically activates the cysteine-rich (C1) domain-containing proteins Ras guanyl nucleotide-releasing protein and PKC- (23)(24)(25) resulting in the activation of the Ras-ERK-AP-1 and NF-B pathways, respectively. In addition, expression of dominant-negative Ras in the Jurkat T cell line inhibited the induction of CD69, thus emphasizing the critical role Ras plays in the TCR/CD3-mediated expression of this early T cell activation marker (26).…”

Activation of diacylglycerol kinase α is required for VEGF-induced angiogenic signaling in vitro

“…Thus Dgk enzymes may act both as terminators of DGmediated signaling and as activators of PA-mediated signals. Indeed, activation of Dgk enzymes has been reported to downregulate DG-regulated enzymes such as PKCs and Ras GTP releasing proteins (RasGRP), respectively, in platelets and T cells (De Chaffoy de Courcelles et al, 1989;Jones et al, 2002;Zhong et al, 2002). On the other hand, activation of Dgk-a has been reported to convey proliferative and motility signals, respectively, in IL-2-stimulated T lymphocytes and in HGF-stimulated endothelial cells (Flores et al, 1996;Cutrupi et al, 2000).…”