Regulatory role of diacylglycerol kinase γ in macrophage differentiation of leukemia cells

Yamada, Katsushi; Sakane, Fumio; Imai, Shin Ichi; Tsushima, Shuichi; Murakami, Tomohiro; Kanoh, Hideo

doi:10.1016/s0006-291x(03)00713-7

Cited by 32 publications

(28 citation statements)

References 28 publications

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“…Thus, we used this mutant as a constitutively active mutant. Indeed, our recent work showed that the effects of overexpression of this mutant in HL-60 cells are markedly stronger than those of wild-type DGK␥ (29). We found that the expression of DGK␥-G494D markedly induced formation of lamellipodia/membrane ruffles in the absence of growth factor stimulation ( Fig.…”

Section: D)mentioning

confidence: 54%

“…Recently, we provided results suggesting that DGK␥ negatively regulates macrophage differentiation of human leukemia HL-60 and U937 cells through its catalytic action (29). Moreover, we found that after phorbol ester treatment, DGK␥ translocates from the cytoplasm to the cell periphery, resulting in its co-localization with F-actin.…”

mentioning

confidence: 84%

“…Plasmid Constructs-The kinase-dead (DGK␣-G435D and DGK␥-G494D) and constitutively active (DGK␣-(⌬1-192) and DGK␥-(⌬1-259)) versions of pig DGK␣ and human DGK␥ were generated as described previously (22,29). The cDNA encoding DGK␤-(⌬1-232) (constitutively active version) was generated from a rat DGK␤ cDNA clone (19) by PCR and subcloned into pEGFP-C3 (BD Biosciences, Tokyo) at the SalI/ BamHI sites.…”

Section: Methodsmentioning

confidence: 99%

“…We recently provided results suggesting that DGK␥ negatively regulates macrophage differentiation of HL-60 and U937 cells through its catalytic action (29). Extensive reorganization of the cytoskeletal networks is closely linked to the acquisition of the macrophage-specific phenotypes (53).…”

Section: Dgk␥ Operates As An Upstreammentioning

confidence: 99%

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Diacylglycerol Kinase γ Serves as an Upstream Suppressor of Rac1 and Lamellipodium Formation

Tsushima

Kai

Yamada

et al. 2004

Journal of Biological Chemistry

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Nine diacylglycerol kinase (DGK) isozymes have been identified. However, our knowledge of their individual functions is still limited. Here, we demonstrate the role of DGK␥ in regulating Rac1-governed cell morphology. We found that the expression of kinase-dead DGK␥, which acts as a dominant-negative mutant, and inhibition of endogenous DGK␥ activity with R59949 induced lamellipodium and membrane ruffle formation in NIH3T3 fibroblasts in the absence of growth factor stimulation. Reciprocally, lamellipodium formation induced by plateletderived growth factor was significantly inhibited upon expression of constitutively active DGK␥. Moreover, the constitutively active DGK␥ mutant suppressed integrinmediated cell spreading. These effects are isoform-specific because, in the same experiments, none of the corresponding mutants of DGK␣ and DGK␤, closely related isoforms, affected cell morphology. These results suggest that DGK␥ specifically participates in the Rac1-mediated signaling pathway leading to cytoskeletal reorganization. In support of this, DGK␥ co-localized with dominant-active Rac1 especially in lamellipodia. Moreover, we found that endogenous DGK␥ was physically associated with cellular Rac1. Dominant-negative Rac1 expression blocked the lamellipodium formation induced by kinase-dead DGK␥, indicating that DGK␥ acts upstream of Rac1. This model is supported by studies demonstrating that kinase-dead DGK␥ selectively activated Rac1, but not Cdc42. Taken together, these results strongly suggest that DGK␥ functions through its catalytic action as an upstream suppressor of Rac1 and, consequently, lamellipodium/ruffle formation.It is well recognized that a variety of lipid second messengers in low abundance carry out specific tasks for a wide range of biological processes in eukaryotic cells. The cellular concentrations of such signaling lipids must be strictly regulated by the action of metabolic enzymes. Diacylglycerol kinase (DGK) 1 phosphorylates diacylglycerol (DAG) to yield phosphatidic acid (PA) (1). DAG is an established activator of conventional and novel protein kinases C (PKCs), Unc-13, and Ras guanyl nucleotide-releasing protein (2-6). PA has also been reported to regulate a number of signaling proteins such as phosphatidylinositol-4-phosphate 5-kinase, Ras GTPase-activating protein, Raf-1 kinase, atypical PKC, and chimaerins (6 -8). Moreover, specific PA-binding sites have recently been identified in several important proteins such as Raf-1 (9), mTOR (mammalian target of rapamycin) (10), and p47 phox (11). Thus, DGK can potentially participate in a diverse range of cellular events through modulating the balance between two bioactive lipids, DAG and PA.Mammalian DGK is known to exist as a large protein family consisting of nine isozymes classified into five subtypes according to their structural features (12-15). These subfamilies can be characterized by the presence of a variety of regulatory domains of known and/or predicted functions, clearly indicating their distinct functions and regulatory mecha...

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Section: D)mentioning

confidence: 54%

mentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: Dgk␥ Operates As An Upstreammentioning

confidence: 99%

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Diacylglycerol Kinase γ Serves as an Upstream Suppressor of Rac1 and Lamellipodium Formation

Tsushima

Kai

Yamada

et al. 2004

Journal of Biological Chemistry

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“…19) DGKγ is highly expressed in the cerebellum and has functional roles in the development of neurons. 20) DGKγ is also reported to regulate macrophage differentiation 21) and mast cell degranulation. 22) DGKδ is suggested to contribute to insulin resistance in the progression of type 2 diabetes.…”

Section: Function and Regulation Of Dgkmentioning

confidence: 99%

Diacylglycerol Signaling Pathway in Pancreatic β-Cells: An Essential Role of Diacylglycerol Kinase in the Regulation of Insulin Secretion

Kaneko

Ishikawa

2015

Biological & Pharmaceutical Bulletin

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The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy

Curtis¹,

Scholfield

2004

Diabetes Metabolism Res

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Diabetic retinopathy is one of the most common complications of diabetes and is a major cause of new blindness in the working-age population of developed countries. While the exact pathogenic basis of this condition remains ill defined, it is clear that hyperglycaemia is a critical factor in its aetiology. Protein kinase C (PKC) activation is one of the sequelae of hyperglycaemia and it is thought to play an important role in the development of diabetic complications. This review questions the currently held dogma that PKC stimulation in diabetes is solely mediated through the overproduction of palmitate and oleate enriched diacylglycerols. Blood glucose concentrations are closely tracked by changes in the levels of free fatty acids and these, in addition to oxidative stress, may account for the aberrant activation of PKCs in diabetes. Little is known about why PKCs fail to downregulate in diabetes and efforts should be directed towards acquiring such information. Considerable evidence implicates the PKCbeta isoform in the pathogenesis of diabetic retinopathy, but other isoforms may also be of relevance. In addition to PKCs, it is evident that novel diacyglycerol-activated non-kinase receptors could also play a role in the development of diabetic complications. Therapeutic agents have been developed to inhibit specific PKC isoforms and PKCbeta antagonists are currently undergoing clinical trials to test their toxicity and efficacy in suppressing diabetic complications. The likely impact of these drugs in the treatment of diabetic patients is considered.

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Regulatory role of diacylglycerol kinase γ in macrophage differentiation of leukemia cells

Cited by 32 publications

References 28 publications

Diacylglycerol Kinase γ Serves as an Upstream Suppressor of Rac1 and Lamellipodium Formation

Diacylglycerol Kinase γ Serves as an Upstream Suppressor of Rac1 and Lamellipodium Formation

Diacylglycerol Signaling Pathway in Pancreatic β-Cells: An Essential Role of Diacylglycerol Kinase in the Regulation of Insulin Secretion

The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy

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