Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that convert DAG to phosphatidic acid (PA), the physiologic functions of which have been poorly defined. We report here that DGK ␣ and synergistically promote T cell maturation in the thymus. Absence of both DGK␣ and (DGK␣ ؊/؊ ؊/؊ ) results in a severe decrease in the number of CD4 ؉ CD8 ؊ and CD4 ؊ CD8 ؉ single-positive thymocytes correlating with increased DAG-mediated signaling. Positive selection, but not negative selection, is impaired in DGK␣ ؊/؊ ؊/؊ mice. The developmental blockage in DGK␣ ؊/؊ ؊/؊ mice can be partially overcome by treatment with PA. Furthermore, decreased DGK activity also promotes thymic lymphomagenesis accompanying elevated Ras and Erk1/2 activation. Our data demonstrate a synergistic and critical role of DGK isoforms in T cell development and tumor suppression, and indicate that DGKs not only terminate DAG signaling but also initiate PA signaling in thymocytes to promote positive selection.phosphatidic acid ͉ signaling ͉ tumorigenesis D iacylglycerol (DAG) kinases (DGKs) are a family of enzymes that catalyze phosphorylation of DAG, converting it to phosphatidic acid (PA). Ten DGK isoforms have been identified in mammals and are divided into 5 subtypes based on unique structural features (1, 2). Within a single tissue, multiple DGK isoforms can be expressed. A notable feature of the DGK-mediated reaction is that both the substrate, DAG, and the product, PA, can be important second messengers. DAG can associate with Ras guanyl nucleotide-releasing proteins (RasGRPs), protein kinase Cs (PKCs), protein kinase Ds, chimaerins, and Munc-13s through their cysteine-rich (C1) domains (3). PA has been reported to bind to the SH-2 domain containing tyrosine phosphatase-1 (SHP-1), mammalian target of Rapamycin (mTOR), cAMP-specific phosphodiesterase 4 (PDE4), protein phosphatase-1 (PP-1), son of sevenless (Sos), and type I phosphatidylinositol 4-phosphate 5-kinase (PI5K) (4 -8). Through the regulation of the activities and subcellular localizations of these signaling molecules, DAG and PA play critical roles in signaling from many cell surface receptors (3, 4). It has been hypothesized that DGKs act as crucial regulators of receptor signaling and cellular function by modulating DAG and PA concentrations. However, the physiologic importance of most DGKs and the role of DGK-derived PA in receptor signaling have been poorly defined.T cell maturation in the thymus occurs through CD4 Ϫ CD8 Ϫ double-negative (DN) to CD4 ϩ CD8 ϩ double-positive (DP) and finally to the CD4 ϩ CD8 Ϫ or CD4 Ϫ CD8 ϩ single-positive (SP) stage (9). Engagement of TCR expressed on DP thymocytes with self-peptide presented by MHCs on thymic stromal cells and bone marrow-derived dendritic cells induces intracellular signaling that can lead to either maturation (positive selection) or cell death (negative selection). In general, TCRs with high affinity to self-antigens elicit strong signals directing negative selection, whereas TCRs with low affinity to self-antigens induce...

Juvenile neuronal ceroid lipofuscinosis (JNCL) belongs to the neuronal ceroid lipofuscinoses characterized by blindness/ seizures/motor/cognitive decline and early death. JNCL is caused by CLN3 gene mutations that negatively modulate cell growth/apoptosis.

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