Nuclear Diacylglycerol Kinase-θ Is Activated in Response to α-Thrombin

Bregoli, Lisa; Baldassare, Joseph J.; Raben, Daniel M.

doi:10.1074/jbc.m101501200

Cited by 48 publications

(49 citation statements)

References 50 publications

(64 reference statements)

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“…Stimulation of aortic SMC with thrombin leads to a rapid and transient activation of PKD, occurring within seconds of thrombin stimulation of aortic SMC. Interestingly, PKD is activated more rapidly than other kinase cascades induced by thrombin, including Elk1 (23), NF B (24), and nuclear diacylglycerol kinase (25). Thus, PKD activation is one of the earliest events induced by thrombin in living cells.…”

Section: Discussionmentioning

confidence: 99%

Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

Tan¹,

Xu²,

Ohba³

et al. 2003

Journal of Biological Chemistry

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Thrombin plays a critical role in hemostasis, thrombosis, and inflammation. However, the responsible intracellular signaling pathways triggered by thrombin are still not well defined. We report here that thrombin rapidly and transiently induces activation of protein kinase D (PKD) in aortic smooth muscle cells. Our data demonstrate that protein kinase C (PKC) inhibitors completely block thrombin-induced PKD activation, suggesting that thrombin induces PKD activation via a PKC-dependent pathway. Furthermore, our results show that thrombin rapidly induces PKC␦ phosphorylation and that the PKC␦-specific inhibitor rottlerin blocks thrombin-induced PKD activation, suggesting that PKC␦ mediates the thrombin-induced PKD activation. Using dominant negative approaches, we demonstrated that expression of a dominant negative PKC␦ inhibits the phosphorylation and activation of PKD induced by thrombin, whereas neither PKC⑀ nor PKC affects thrombin-induced PKD activation. In addition, our results of co-immunoprecipitation assays showed that PKD forms a complex with PKC␦ in smooth muscle cells. Taken together, the findings of the present study demonstrate that thrombin induces activation of PKD and reveal a novel role of PKC␦ in mediating thrombininduced PKD activation in vascular smooth muscle cells.Thrombin belongs to the multifunctional serine protease family and plays an important role in the blood coagulation cascade through the cleavage of fibrinogen to fibrin (1, 2). Thrombin also exerts direct effects on cells to regulate platelet aggregation, endothelial cell activation, and smooth muscle cell (SMC) 1 proliferation via interactions with members of the protease-activated receptor (PAR) family, such as PAR1, PAR2, PAR3, and PAR4, known as G-protein-coupled receptors (2, 3). However, the intracellular signaling cascades downstream from the thrombin receptors are surprisingly complex and are still not well understood.Protein kinase D (PKD), also known as protein kinase C (4, 5), is a newly described serine/threonine protein kinase with unique structural, enzymological, and regulatory properties that are different from those of the PKC family members. The most distinct characteristics of PKD are the presence of a catalytic domain distantly related to Ca 2ϩ -regulated kinases, a pleckstrin homology domain within the regulatory region, and a highly hydrophobic stretch of amino acids in its N-terminal region (6, 7).PKD can be activated by a variety of stimuli including biologically active phorbol esters, growth factors, and T-and B-cell receptor agonists via PKC-dependent pathways (6,7). PKD activation appears to involve the phosphorylation of Ser-744 and Ser-748 within the activation loop of the catalytic domain as well as the autophosphorylation of Ser-916 (6). PKD has been implicated in the regulation of a variety of cellular functions including NF B-mediated gene expression, Na ϩ /H ϩ antiport activity, Golgi organization and function, and protein transport (7,8). The aim of the present study is to determine whether and h...

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Section: Discussionmentioning

confidence: 99%

Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

Tan¹,

Xu²,

Ohba³

et al. 2003

Journal of Biological Chemistry

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“…Particularly important will be determining where the lipid substrate binds, the points of contact of the enzyme with lipid surfaces, and how the substrates are transferred from lipid bilayers into the catalytic pocket. Both SK and DGKs (a, b, g, z, L, u) are strongly activated in vitro by anionic phospholipids (96,(114)(115)(116)(117). This results in an increase in V max .…”

Section: Enzymology Of Dgksmentioning

confidence: 99%

The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function

Wattenberg

Pitson

Raben

2006

Journal of Lipid Research

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114

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The sphingosine and diacylglycerol kinases form a superfamily of structurally related lipid signaling kinases. One of the striking features of these kinases is that although they are clearly involved in agonist-mediated signaling, this signaling is accomplished with only a moderate (and sometimes no) increase in the enzymatic activity of the enzymes. Here, we summarize findings that indicate that signaling by these kinases is strongly dependent on their localization to specific intracellular sites rather than on increases in enzyme activity. Both the substrates and products of these enzymes are bioactive lipids. Moreover, many of the metabolic enzymes that act on these lipids are found in specific organelles. Therefore, changes in the membrane localization of these signaling kinases have profound effects not only on the production of signaling lipid phosphates but also on the metabolism of the upstream signaling lipids.-Wattenberg, B. W., S. M. Pitson, and D. M. Raben. The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function.

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“…DGK isoforms have been implicated in various other cellular processes including inhibition of Rap1 signaling ( 9 ) and retinoblastoma-mediated cell cycle control ( 10 ). DGK is activated by nerve growth factor in PC12 cells ( 11 ) and thrombin in IIC9 fi broblasts ( 12,13 ), whereas DGK promotes myogenesis in C2C12 cells ( 14 ) and DGK ␥ plays a role in regulating the cell cycle in CHO-K cells ( 15 ).…”

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confidence: 99%

cAMP-stimulated transcription of DGKθ requires steroidogenic factor 1 and sterol regulatory element binding protein 1

Cai

Sewer

2013

Journal of Lipid Research

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( 4 ). DGK -null mice exhibit several neural abnormalities, including a higher resistance of electroconvulsive shock ( 5 ) and increased cyclooxygenase 2 and tyrosine hydroxylase expression ( 6 ), suggesting a role for DGK in regulating synaptic activity. Mice lacking DGK ␣ ( 7 ) or DGK ( 8 ) exhibit enhanced T cell function and demonstrate a role for these kinases in controlling DAG metabolism during the immune response. DGK isoforms have been implicated in various other cellular processes including inhibition of Rap1 signaling ( 9 ) and retinoblastoma-mediated cell cycle control ( 10 ). DGK is activated by nerve growth factor in PC12 cells ( 11 ) and thrombin in IIC9 fi broblasts ( 12, 13 ), whereas DGK promotes myogenesis in C2C12 cells ( 14 ) and DGK ␥ plays a role in regulating the cell cycle in CHO-K cells ( 15 ).To date, 10 mammalian DGKs have been identifi ed that are divided into fi ve groups based on functional domains ( 16,17 ). However, all isoforms contain cysteine-rich zinc fi nger-like structures, a conserved catalytic region ( 18-21 ). DGK , the sole member of group V, is comprised of three cysteine-rich domains (CRDs), a proline/glycine-rich domain at its N terminus, and a pleckstrin homology (PH) with an overlapping Ras-binding domain ( 22 ). While the functions of many of the other domains in DGK are unclear, the catalytic activity requires all domains of the enzyme ( 23 ). It has been postulated that the CRDs of the enzyme are required both for correct folding of the protein and for substrate presentation ( 23 ). Mutation of the CRD of DGK diminishes DAG-induced translocation of the enzyme to the plasma membrane ( 24 ); whereas the interaction between DGK and the nuclear receptor steroidogenic factor 1 (SF1) requires the PH domain ( 25 ). Abstract Diacylglycerol kinase (DGK) is

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Nuclear Diacylglycerol Kinase-θ Is Activated in Response to α-Thrombin

Cited by 48 publications

References 50 publications

Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function

cAMP-stimulated transcription of DGKθ requires steroidogenic factor 1 and sterol regulatory element binding protein 1

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