Both the C1 domain and a basic amino acid cluster at the C-terminus are important for the neurite and branch induction ability of DGKβ

Kano, Takuya; Kouzuki, Takeshi; Mizuno, Seitoku; Ueda, Shuji; Yamanoue, Minoru; Sakane, Fumio; Saito, Naoaki; Shirai, Yasuhito

doi:10.1016/j.bbrc.2014.03.113

Cited by 9 publications

(14 citation statements)

References 34 publications

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“…[1][2][3][4] Type I DGK isozymes (DGKs α, β, and γ) commonly contain a recoverin homology domain, two Ca 2+ -binding EF-hand motifs and two C1 domains in addition to a catalytic domain. 5,6 DGKβ, which is highly expressed in the brain, 7 was reported to be involved in spinogenesis and spine branching 8,9 and its knockout (KO) mouse model showed bipolar disorder (mania)-like behaviors. 10,11 DGKγ, which is strongly expressed in the retina and brain, 12,13 is known to regulate remodeling of the cytoskeleton via Rac1 and β2-chimaerin (Rac-GTPase activating protein) 14,15 and cell growth.…”

Section: Introductionmentioning

confidence: 99%

Diacylglycerol kinase α‐selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines

Yamaki

Akiyama

Murakami

et al. 2018

J of Cellular Biochemistry

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Diacylglycerol (DG) kinase (DGK), which phosphorylates DG to generate phosphatidic acid (PA), consists of ten isozymes (α-к). Recently, we identified a novel small molecule inhibitor, CU-3, that selectively inhibits the activity of the α isozyme. In addition, we newly obtained Compound A, which selectively and strongly inhibits type I DGKs (α, β, and γ). In the present study, we demonstrated that both CU-3 and Compound A induced apoptosis (caspase 3/7 activity and DNA fragmentation) and viability reduction of AKI melanoma cells. Liquid chromatography-mass spectrometry revealed that the production of 32:0-and 34:0-PA species was commonly attenuated by CU-3 and Compound A, suggesting that lower levels of these PA molecular species are involved in the apoptosis induction and viability reduction of AKI cells. We determined the effects of the DGKα inhibitors on several other cancer cell lines derived from refractory cancers. In addition to melanoma, the DGKα inhibitors enhanced caspase 3/7 activity and reduced the viability of hepatocellular carcinoma, glioblastoma, and pancreatic cancer cells, but not breast adenocarcinoma cells.Interestingly, Western blot analysis indicated that the DGKα expression levels were positively correlated with the sensitivity to the DGK inhibitors. Because both CU-3 and Compound A induced interleukin-2 production by T cells, it is believed that these two compounds can enhance cancer immunity. Taken together, our results suggest that DGKα inhibitors are promising anticancer drugs. K E Y W O R D S apoptosis, cancer, diacylglycerol kinase (DGK), inhibitor, melanoma, phosphatidic acid (PA)

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Section: Introductionmentioning

confidence: 99%

Diacylglycerol kinase α‐selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines

Yamaki

Akiyama

Murakami

et al. 2018

J of Cellular Biochemistry

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“…Additionally, DGKε also regulates cerebellar motor coordination by DG metabolization with DG lipase a (DGLα) [ 40 ]. DGKβ was characteristically localized at the plasma membrane, which is the hallmark of DGK activation [ 41 ]. DGKβ KO mice showed downregulated postsynaptic long-term potentiation (LTP) at Schaffer-collateral (SC)-CA1 synapses, resulting in impaired cognitive function and hyperactivity [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Western blotting was performed as described previously [ 41 ]. Briefly, the samples (10 μg protein) were subjected to 10% SDS-PAGE, followed by blotting onto a poly-vinylidene difluoride membrane (Millipore, Darmstadt, Germany).…”

Section: Methodsmentioning

confidence: 99%

Precise Regulation of the Basal PKCγ Activity by DGKγ Is Crucial for Motor Coordination

Tsumagari

Maruo

Kakizawa

et al. 2020

IJMS

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Diacylglycerol kinase γ (DGKγ) is a lipid kinase to convert diacylglycerol (DG) to phosphatidic acid (PA) and indirectly regulates protein kinase C γ (PKCγ) activity. We previously reported that the basal PKCγ upregulation impairs cerebellar long-term depression (LTD) in the conventional DGKγ knockout (KO) mice. However, the precise mechanism in impaired cerebellar LTD by upregulated PKCγ has not been clearly understood. Therefore, we first produced Purkinje cell-specific DGKγ KO (tm1d) mice to investigate the specific function of DGKγ in Purkinje cells and confirmed that tm1d mice showed cerebellar motor dysfunction in the rotarod and beam tests, and the basal PKCγ upregulation but not PKCα in the cerebellum of tm1d mice. Then, the LTD-induced chemical stimulation, K-glu (50 mM KCl + 100 µM, did not induce phosphorylation of PKCα and dissociation of GluR2 and glutamate receptor interacting protein (GRIP) in the acute cerebellar slices of tm1d mice. Furthermore, treatment with the PKCγ inhibitor, scutellarin, rescued cerebellar LTD, with the phosphorylation of PKCα and the dissociation of GluR2 and GRIP. In addition, nonselective transient receptor potential cation channel type 3 (TRPC3) was negatively regulated by upregulated PKCγ. These results demonstrated that DGKγ contributes to cerebellar LTD by regulation of the basal PKCγ activity.

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“…Western blotting was performed as described previously (Kano et al, 2014). Briefly, the samples were subjected to 10% SDS-PAGE, followed by blotting onto a poly-vinylidene difluoride membrane (Millipore).…”

Section: Western Blottingmentioning

confidence: 99%

DGKγ Knock-Out Mice Show Impairments in Cerebellar Motor Coordination, LTD, and the Dendritic Development of Purkinje Cells through the Activation of PKCγ

Tsumagari

Kakizawa

Kikunaga

et al. 2020

eNeuro

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Diacylglycerol kinase g (DGKg) regulates protein kinase C (PKC) activity by converting DG to phosphatidic acid (PA). DGKg directly interacts with PKCg and is phosphorylated by PKCg , resulting in the upregulation of lipid kinase activity. PKC dysfunction impairs motor coordination, indicating that the regulation of PKC activity is important for motor coordination. DGKg and PKC are abundantly expressed in cerebellar Purkinje cells. However, the physiological role of DGKg has not been elucidated. Therefore, we developed DGKg knockout (KO) mice and tested their cerebellar motor coordination. In DGKg KO mice, cerebellar motor coordination and long-term depression (LTD) were impaired, and the dendrites of Purkinje cells from DGKg KO mice were significantly retracted. Interestingly, treatment with the cPKC inhibitor Gö6976 (Gö) rescued the dendritic retraction of primary cultured Purkinje cells from DGKg KO mice. In contrast, treatment with the PKC activator 12-o-tetradecanoylphorbol 13-acetate (TPA) reduced morphologic alterations in the dendrites of Purkinje cells from wild-type (WT) mice. In addition, we confirmed the upregulation of PKCg activity in the cerebellum of DGKg KO mice and rescued impaired LTD in DGKg KO mice with a PKCg-specific inhibitor. Furthermore, impairment of motor coordination observed in DGKg KO mice was rescued in tm1c mice with DGKg reexpression induced by the FLP-flippase recognition target (FRT) recombination system. These results indicate that DGKg is involved in cerebellar LTD and the dendritic development of Purkinje cells through the regulation of PKCg activity, and thus contributes to cerebellar motor coordination.

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Both the C1 domain and a basic amino acid cluster at the C-terminus are important for the neurite and branch induction ability of DGKβ

Cited by 9 publications

References 34 publications

Diacylglycerol kinase α‐selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines

Diacylglycerol kinase α‐selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines

Precise Regulation of the Basal PKCγ Activity by DGKγ Is Crucial for Motor Coordination

DGKγ Knock-Out Mice Show Impairments in Cerebellar Motor Coordination, LTD, and the Dendritic Development of Purkinje Cells through the Activation of PKCγ

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