Disease relevance of DGKZ

• Diacylglycerol kinase zeta in hypothalamus interacts with long form leptin receptor. Relation to dietary fat and body weight regulation [1].
• Taken together, our evidence suggests that DGKzeta constitutes a downstream component of the leptin signaling pathway and that reduced hypothalamic DGKzeta mRNA, and possibly activity, is associated with obesity [1].
• This suggests that rapid disappearance of DGKzeta in ischemic neurons is a quite early event precedent to neuronal degeneration in response to ischemia [2].
• Diacylglycerol kinase zeta is involved in the process of cerebral infarction [2].

Psychiatry related information on DGKZ

• In our approach for the analysis of the composition of tau inclusions, we detected the intense binding of anti-diacylglycerol kinase-zeta (DGK-zeta) antibodies to Pick bodies (PBs), which represent tau inclusions in Pick's disease [3].

High impact information on DGKZ

• The nuclear-localization signal of DGK-zeta is located in a region that is homologous to the phosphorylation-site domain of the MARCKS protein [4].
• Reducing nuclear diacylglycerol levels by conditional expression of DGK-zeta attenuates cell growth [4].
• When stimulated in anergy-producing conditions, T cells lacking DGK-alpha or DGK-zeta proliferated and produced interleukin 2 [5].
• Phosphorylation of this motif significantly attenuated coimmunoprecipitation of DGKzeta and PKCalpha and abolished their colocalization in cells, indicating that it negatively regulates binding [6].
• We also show that DGKzeta directly interacts with PKCalpha in a signaling complex and that the binding site in DGKzeta is located within the catalytic domain [6].

Biological context of DGKZ

• Taken together, these results indicate that PKC alpha phosphorylates DGK zeta in cells, and this phosphorylation inhibits its kinase activity to remove cellular DAG, thereby affecting cell growth [7].
• The coding sequence was shown to be derived from alternative splicing of the DGKzeta gene [8].
• We screened a cDNA library from human skeletal muscle and isolated two DGKzeta cDNAs that differed from the 3.5-kb clone originally identified in endothelial cells [8].
• We also isolated a genomic clone of DGKzeta and determined its organization and location; it contains 32 exons, spans approximately 50 kb of genomic sequence, and maps to chromosome 11p11 [8].
• The data show that DGK zeta has strict requirements for intact zinc fingers and the conserved catalytic domain for full enzymatic activity [9].

Anatomical context of DGKZ

• Finally, overexpression of kinase-dead DGK zeta in Jurkat cells prolonged Ras activation after ligation of the T cell receptor [10].
• The level of endogenous syntrophins in the nucleus of HeLa cells also reflected the amount of nuclear DGK-zeta [11].
• In addition, we demonstrate that the activation of DGK-zeta exerts a functional role in the murine gonadotrope LbetaT2 cell line [12].
• DGK-zeta translocates from the cytosol to the nucleus, a process negatively regulated by protein kinase C phosphorylation [11].
• COS-7 cells transfected with the hDGKzeta cDNA express 117-kDa and 114-kDa proteins that react specifically with an antibody to a peptide derived from a unique sequence in hDGK zeta [13].

Associations of DGKZ with chemical compounds

• 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 [14].
• The hDGKzeta displays stereoselectivity for 1,2-diacylglycerol species in comparison to 1,3-diacylglycerol, but does not exhibit any specificity for molecular species of long chain diacylglycerols [13].
• Gonadotropin-releasing hormone-induced activation of diacylglycerol kinase-zeta and its association with active c-src [12].
• Significantly, in wounding assays, DGKzeta, PIP5KIalpha and PIP2 accumulated at the leading edge of migrating A172 cells, where massive actin polymerization is known to occur [15].
• Diacylglycerol kinase zeta regulates phosphatidylinositol 4-phosphate 5-kinase Ialpha by a novel mechanism [15].

Physical interactions of DGKZ

• DGK zeta also coimmunoprecipitated with PKC alpha, suggesting that they reside in a regulated signaling complex [7].

Co-localisations of DGKZ

• We also observed that DGKzeta co-immunoprecipitated and co-localized with PIP5KIalpha, suggesting that they reside in a regulated signaling complex [15].

Regulatory relationships of DGKZ

• Furthermore, activation of PKC alpha by phorbol 12-myristate 13-acetate inhibited the activity of wild-type DGK zeta, but not DGK zeta S/D, in human embryonic kidney 293 cells [7].
• Collectively, our results suggest that gamma 1-syntrophin participates in regulating the subcellular localization of DGK-zeta to ensure correct termination of diacylglycerol signaling [11].
• Down-regulation of endogenous DGKzeta by small interfering RNA in HEK293 cells diminished serum-induced p70S6K phosphorylation, highlighting the role of this isoform in the mTOR pathway [16].
• Here we show that expression of DGKzeta significantly enhances PIP5KIalpha activity in thrombin-stimulated HEK293 cells, and DGK activity is required for this stimulation [15].

Other interactions of DGKZ

• These results suggest that by phosphorylating the MARCKS PSD, PKC alpha attenuates DGK zeta activity [7].
• We demonstrated previously that a peptide corresponding to the myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation site domain (PSD) in DGK zeta was phosphorylated in vitro by an active fragment of protein kinase C (PKC) [7].
• Using reciprocal co-immunoprecipitation we show that there is a significant elevation of the association between catalytically active c-Src with DGK-zeta in both HEK293 cells and murine gonadotrope LbetaT2 cells [12].
• We found that DGK-zeta recruits gamma 1-syntrophin into the nucleus and that the PDZ-binding motif is required [11].
• 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 [14].

Analytical, diagnostic and therapeutic context of DGKZ

• Molecular cloning and characterization of a novel human diacylglycerol kinase zeta [13].
• From Northern blot analysis of multiple tissues, we observed that hDGKzeta mRNA is expressed at highest levels in brain [13].
• Furthermore, we show by in situ hybridization that DGKzeta is expressed in neurons of hypothalamic nuclei known to synthesize Ob-Rb and to participate in energy homeostasis [1].

References