Cloning of a Novel Human Diacylglycerol Kinase (DGKθ) Containing Three Cysteine-rich Domains, a Proline-rich Region, and a Pleckstrin Homology Domain with an Overlapping Ras-associating Domain

Houssa, Brahim; Schaap, Dick; Wal, J van der; Goto, Kaoru; Kondo, Hisatake; Yamakawa, Akira; Shibata, Masao; Takenawa, Tadaomi; Blitterswijk, Wim J. van

doi:10.1074/jbc.272.16.10422

Cited by 104 publications

(105 citation statements)

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“…DGK Enzymatic Assays-DGK activity was measured essentially as described previously (28,44) in the presence of 1 mM deoxycholate, 1 mM phosphatidylserine, 1 mM dioleoylglycerol, and 2 mM [␥-32 P]ATP. Lipids were extracted in chloroform/methanol (1:1), and after phase separation, lipids in the organic phase were separated by silica TLC, using the developing system chloroform/methanol/ammonia/water (45:35:2.5:…”

Section: Methodsmentioning

confidence: 99%

“…Their structural diversity together with their different tissue/cell distribution and subcellular localization, suggests that each DGK isoform may regulate distinct DAG signaling events. We previously identified the type V isotype, DGK, which contains three (instead of two) cysteine-rich domains (CRDs; potential DAG binding sites), a proline-rich region, and a pleckstrin homology domain with an overlapping Ras-associating domain (28). DGK is a cytosolic protein, whose activity is regulated negatively by interaction with RhoA (29) and positively by translocation to the nucleus in response to thrombin stimulation in IIC9 cells (30) and to the plasma membrane in response to noradrenaline in rat mesenteric small arteries (31).…”

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confidence: 99%

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Translocation of Diacylglycerol Kinase θ from Cytosol to Plasma Membrane in Response to Activation of G Protein-coupled Receptors and Protein Kinase C

Baal

Widt

Divecha

et al. 2005

Journal of Biological Chemistry

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Diacylglycerol kinase (DGK) phosphorylates the second messenger diacylglycerol (DAG) to phosphatidic acid. We previously identified DGK as one of nine mammalian DGK isoforms and reported on its regulation by interaction with RhoA and by translocation to the plasma membrane in response to noradrenaline. Here, we have investigated how the localization of DGK, fused to green fluorescent protein, is controlled upon activation of G protein-coupled receptors in A431 cells. Extracellular ATP, bradykinin, or thrombin induced DGK translocation from the cytoplasm to the plasma membrane within 2-6 min. This translocation, independent of DGK activity, was preceded by protein kinase C (PKC) translocation and was blocked by PKC inhibitors. Conversely, activation of PKC by 12-O-tetradecanoylphorbol-13-acetate induced DGK translocation. Membrane-permeable DAG (dioctanoylglycerol) also induced DGK translocation but in a PKC (staurosporin)-independent fashion. Mutations in the cysteinerich domains of DGK abrogated its hormone-and DAGinduced translocation, suggesting that these domains are essential for DAG binding and DGK recruitment to the membrane. We show that DGK interacts selectively with and is phosphorylated by PKC⑀ and -and that peptide agonist-induced selective activation of PKC⑀ directly leads to DGK translocation. Our data are consistent with the concept that hormone-induced PKC activation regulates the intracellular localization of DGK, which may be important in the negative regulation of PKC⑀ and/or PKC activity.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Translocation of Diacylglycerol Kinase θ from Cytosol to Plasma Membrane in Response to Activation of G Protein-coupled Receptors and Protein Kinase C

Baal

Widt

Divecha

et al. 2005

Journal of Biological Chemistry

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“…Class IV isozymes contain four C-terminal ankyrin repeats, a PDZ (postsynaptic density protein-95/Discs large/ zona occludens-1) domain, and a nuclear localization signal (NLS) which overlaps with a region homologous to the phosphorylation site of the PKC substrate "myristoylated alanine-rich C-kinase substrate (MARCKS)" Goto and Kondo 1996). Class V DGKθ has a region with weak homology to PH domain, which overlaps with a Ras-associating domain (Houssa et al 1997). …”

Section: Molecular Cloning and Dgk Isozymesmentioning

confidence: 99%

“…Class I comprises the α (Sakane et al 1990;Schaap et al 1990), β (Goto and Kondo 1993), and γ (Goto et al 1994;Kai et al 1994); class II the δ (Sakane et al 1996), η (Klauck et al 1996), and κ (Imai et al 2005); class III the ε ; class IV the ζ Goto and Kondo 1996) and ι (Ding et al 1998); class V the θ (Houssa et al 1997). Furthermore, alternative splice variants have been reported in several of such isozymes as DGKβ (Caricasole et al 2002), -γ (Kai et al 1994), -δ , -η (Murakami et al 2003), -ι (Ito et al 2004), and -ζ (Ding et al 1997).…”

Section: Molecular Cloning and Dgk Isozymesmentioning

confidence: 99%

Lipid Messenger, Diacylglycerol, and its Regulator, Diacylglycerol Kinase, in Cells, Organs, and Animals: History and Perspective

Goto

Hozumi

Nakano

et al. 2008

Tohoku J. Exp. Med.

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Diacylglycerol kinase (DGK) metabolizes diacylglycerol (DG), a glycerolipid containing two acyl chains, to convert phosphatidic acid. DG is produced through phosphoinositide turnover within the membrane and is well known to act as a second messenger that modulates the activity of protein kinase C in the cellular signal transduction. Recent studies have revealed that DG also activates several proteins, including Ras guanine-nucleotide releasing protein and ion channels such as transient receptor potential proteins. Therefore, DGK is thought to participate in a number of signaling cascades by modulating levels of DG. Previous studies have disclosed that DGK is composed of a family of the isozymes, which differ in the structure, enzymological property, gene expression and localization, subcellular localization, and binding molecules. The present review focuses on the stories of phosphoinositide turnover and DG, including historical views, structural features, metabolism, and relevant cellular phenomena, together with the characteristics of DGK isozymes and the pathophysiological fi ndings on animal studies using knockout mice and models for human diseases. Now it is being revealed that the structural and functional diversity and heterogeneity of and around DGK support the proper arrangement of the complex signal transduction machinery.phosphoinositide; diacylglycerol; second messenger; diacylglycerol kinase; isozyme; animal models. Tohoku

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“…To date, nine subtypes of mammalian DGKs have been cloned (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). All DGK isozymes consist of a conserved catalytic domain and two or three cysteine-rich C1 domains designated as C1A, C1B, and C1C (16).…”

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Synthesis and Phorbol Ester Binding of the Cysteine-rich Domains of Diacylglycerol Kinase (DGK) Isozymes

Shindo¹,

Irie

Masuda

et al. 2003

Journal of Biological Chemistry

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Diacylglycerol kinase (DGK) and protein kinase C (PKC) are two distinct enzyme families associated with diacylglycerol. Both enzymes have cysteine-rich C1 domains (C1A, C1B, and C1C) in the regulatory region. Although most PKC C1 domains strongly bind phorbol esters, there has been no direct evidence that DGK C1 domains bind phorbol esters. We synthesized 11 cysteine-rich sequences of DGK C1 domains with good sequence homology to those of the PKC C1 domains. Among them, only DGK␥-C1A and DGK␤-C1A exhibited significant binding to phorbol 12,13-dibutyrate (PDBu). Scatchard analysis of rat-DGK␥-C1A, human-DGK␥-C1A, and human-DGK␤-C1A gave K d values of 3.6, 2.8, and 14.6 nM, respectively, suggesting that DGK␥ and DGK␤ are new targets of phorbol esters. An A12T mutation of human-DGK␤-C1A enhanced the affinity to bind PDBu, indicating that the ␤-hydroxyl group of Thr-12 significantly contributes to the binding. The K d value for PDBu of FLAG-tagged whole rat-DGK␥ (4.4 nM) was nearly equal to that of rat-DGK␥-C1A (3.6 nM). Moreover, 12-O-tetradecanoylphorbol 13-acetate induced the irreversible translocation of whole rat-DGK␥ and its C1B deletion mutant, not the C1A deletion mutant, from the cytoplasm to the plasma membrane of CHO-K1 cells. These results indicate that 12-O-tetradecanoylphorbol 13-acetate binds to C1A of DGK␥ to cause its translocation.Diacylglycerol kinase (DGK) 1 and protein kinase C (PKC) both interact with the second messenger diacylglycerol (DG) (1, 2). DGK phosphorylates DG to produce phosphatidic acid, whereas PKC is allosterically activated by DG in the presence of phosphatidylserine. Therefore, DGK may inhibit the activation of PKC by attenuating DG levels, contributing to the regulation of intracellular signal transduction.To date, nine subtypes of mammalian DGKs have been cloned (3-15). All DGK isozymes consist of a conserved catalytic domain and two or three cysteine-rich C1 domains designated as C1A, C1B, and C1C (16). These isozymes are classified into five classes according to the other functional domains (Fig. 1). The class I isozymes (DGK␣, -␤, and -␥) have calcium binding domains (EF-hands). The class II isozymes (DGK␦ and -) have a pleckstrin homology domain at the N terminus, and their catalytic region is split into two domains unlike the other DGK isozymes. DGK⑀ has a simple structure and is classified as a class III isozyme. The class IV isozymes DGK and have a myristoylated alanine-rich C kinase substrate homology domain and four ankyrin repeats. DGK , which has three C1 domains unlike other DGK and PKC isozymes, is the only isozyme in class V.The similarity between DGK and PKC isozymes in structure is in the cysteine-rich C1 domains. Recent investigations using NMR spectroscopy and x-ray crystallography have revealed the three-dimensional structure of C1B domains of PKC␣, PKC␥,. Each PKC C1 domain has six conserved cysteines and two histidines in the typical core structure HX 12 CX 2 CX 13-14 CX 2 CX 4 HX 2 CX 7 C (where X is any amino acid) that coordinates two atoms of zinc in...

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Cloning of a Novel Human Diacylglycerol Kinase (DGKθ) Containing Three Cysteine-rich Domains, a Proline-rich Region, and a Pleckstrin Homology Domain with an Overlapping Ras-associating Domain

Cited by 104 publications

References 58 publications

Translocation of Diacylglycerol Kinase θ from Cytosol to Plasma Membrane in Response to Activation of G Protein-coupled Receptors and Protein Kinase C

Translocation of Diacylglycerol Kinase θ from Cytosol to Plasma Membrane in Response to Activation of G Protein-coupled Receptors and Protein Kinase C

Lipid Messenger, Diacylglycerol, and its Regulator, Diacylglycerol Kinase, in Cells, Organs, and Animals: History and Perspective

Synthesis and Phorbol Ester Binding of the Cysteine-rich Domains of Diacylglycerol Kinase (DGK) Isozymes

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