Regulation of DGK‐θ

Tu-Sekine, Becky; Raben, Daniel M.

doi:10.1002/jcp.21813

Cited by 10 publications

(8 citation statements)

References 74 publications

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“…For example, the most commonly used DGKa inhibitors, R59949 and R59022, broadly attenuate other DGK isotypes, such as DGKe, DGKq, DGKg, DGKk, and DGKd (28). Thus, clinical application of such inhibitors would probably be associated with undesirable effects; it is known that mutations in some of the isotypes, such as DGKq and DGKd, cause neuronal defects (44,45). Lastly, systemic administration of DGK inhibitors would also pose significant safety concerns, given that systematic deficiency of DGKa and DGKz has been shown to significantly impair T-cell development in mice and that DGKz has been suggested to protect hippocampal neurons from ischemia (46,47).…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells

et al. 2018

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The efficacy of T-cell therapy is inhibited by various tumor-associated immunosuppressive ligands and soluble factors. Such inhibitory signals turn specific T-cell signaling pathways on or off, impeding the anticancer functions of T cells. Many studies have focused on PD-1 or CTLA-4 blockade to invigorate T-cell functions through CD28/B7 signaling, but obtaining robust clinical outcomes remains challenging. In this study, we use CRISPR/Cas9 to potentiate T-cell function by increasing CD3 signaling via knockout of diacylglycerol kinase (DGK), an enzyme that metabolizes diacylglycerol to phosphatidic acid. Knockout of DGK augmented the effector functions of CAR-T cells via increased TCR signaling. DGK knockout from CAR-T cells rendered them resistant to soluble immunosuppressive factors such as TGFβ and prostaglandin E2 and sustained effector functions under conditions of repeated tumor stimulation. Moreover, DGK knockout caused significant regression of U87MGvIII glioblastoma tumors through enhanced effector functions in a xenograft mouse model. Collectively, our study shows that knockout of DGK effectively enhances the effector functions of CAR-T cells, suggesting that CRISPR/Cas9-mediated knockout of DGK could be applicable as part of a multifaceted clinical strategy to treat solid cancers. This novel study demonstrates efficient ablation of diacylglycerol kinase in human CAR-T cells that leads to improved antitumor immunity and may have significant impact in human cancer immunotherapy. .

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Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells

et al. 2018

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“…DGKγ, which is predominantly localized in Purkinje cells and hippocampus, is present at birth and then gradually increased [13,38]. The mRNA expression of DGKθ is the highest in cerebellum and hippocampus [18] and it is suggested that DGKθ is involved in neurotransmitter release [84]. However, further examination would be necessary to understand physiological functions of DGKα, γ, and θ in brain.…”

Section: Reviewmentioning

confidence: 99%

Diacylglycerol kinase as a possible therapeutic target for neuronal diseases

Shirai

Saito

2014

J Biomed Sci

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Diacylglycerol kinase (DGK) is a lipid kinase converting diacylglycerol to phosphatidic acid, and regulates many enzymes including protein kinase C, phosphatidylinositol 4-phosphate 5-kinase, and mTOR. To date, ten mammalian DGK subtypes have been cloned and divided into five groups, and they show subtype-specific tissue distribution. Therefore, each DGK subtype is thought to be involved in respective cellular responses by regulating balance of the two lipid messengers, diacylglycerol and phosphatidic acid. Indeed, the recent researches using DGK knockout mice have clearly demonstrated the importance of DGK in the immune system and its pathophysiological roles in heart and insulin resistance in diabetes. Especially, most subtypes show high expression in brain with subtype specific regional distribution, suggesting that each subtype has important and unique functions in brain. Recently, neuronal functions of some DGK subtypes have accumulated. Here, we introduce DGKs with their structural motifs, summarize the enzymatic properties and neuronal functions, and discuss the possibility of DGKs as a therapeutic target of the neuronal diseases.

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“…The optimal activation of DGKθ may require both polybasic protein and acidic phospholipid cofactors, which have been shown to stimulate DGKθ synergistically in vitro [25,26]. These multiple regulatory mechanisms enable DGKθ to mediate signals from a wide variety of extracellular ligands [24,27] including epidermal growth factor [28], nerve growth factor [29], α-thrombin [30], and adenosine [31]. …”

Section: Introductionmentioning

confidence: 99%

The expression of diacylglycerol kinase theta during the organogenesis of mouse embryos

et al. 2013

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BackgroundDiacylglycerol kinase (DGK) is a key enzyme that regulates diacylglycerol (DG) turnover and is involved in a variety of physiological functions. The isoform DGKθ has a unique domain structure and is the sole member of type V DGK. To reveal the spatial and temporal expression of DGKθ we performed immunohistochemical staining on paraffin sections of mouse embryos.ResultsAt an early stage of development (E10.5 and 11.5), the expression of DGKθ was prominently detected in the brain, spinal cord, dorsal root ganglion, and limb bud, and was also moderately detected in the bulbus cordis and the primordium of the liver and gut. At later stages (E12.5 and 14.5), DGKθ expression persisted or increased in the neocortex, epithalamus, hypothalamus, medulla oblongata, and pons. DGKθ was also evident in the epidermis, and nearly all epithelia of the oropharyngeal membrane, digestive tract, and bronchea. At prenatal developmental stages (E16.5 and E18.5), the expression pattern of DGKθ was maintained in the central nervous system, intestine, and kidney, but was attenuated in the differentiated epidermis.ConclusionThese results suggest that DGKθ may play important physiological roles not only in the brain, but also in diverse organs and tissues during the embryonic stages.

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Regulation of DGK‐θ

Cited by 10 publications

References 74 publications

CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells

CRISPR/Cas9-Mediated Knockout of DGK Improves Antitumor Activities of Human T Cells

Diacylglycerol kinase as a possible therapeutic target for neuronal diseases

The expression of diacylglycerol kinase theta during the organogenesis of mouse embryos

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