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

Baal, J. van; Widt, John de; Divecha, Nullin; Blitterswijk, Wim J. van

doi:10.1074/jbc.m409301200

Cited by 70 publications

(69 citation statements)

References 56 publications

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“…We show that, although they are atypical, the DGK␣ C1 domains represent an essential module in plasma membrane interaction through protein and/or lipid binding. Our experiments agree with previous reports using the DGK and DGK isoforms (9,30) and confirm that the essential role of the C1 domains for membrane localization is a general characteristic of the DGK family. The precise function of C1 domains in DGK membrane binding is not known, although they have been identified as sites of interactions with lipids (31) and proteins (7), as shown for atypical C1 domains in other proteins such as Raf (32).…”

Section: Discussionsupporting

confidence: 93%

Role of the Diacylglycerol Kinase α-Conserved Domains in Membrane Targeting in Intact T Cells

Merino¹,

Sanjuán²,

Moraga

et al. 2007

Journal of Biological Chemistry

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Diacylglycerol kinase (DGK) phosphorylates diacylglycerol to phosphatidic acid, modifying the cellular levels of these two lipid mediators. Ten DGK isoforms, grouped into five subtypes, are found in higher organisms. All contain a conserved C-terminal domain and at least two cysteine-rich motifs of unknown function. DGK␣ is a type I enzyme that acts as a negative modulator of diacylglycerol-based signals during T cell activation. Here we studied the functional role of the DGK␣ domains using mutational analysis to investigate membrane binding in intact cells. We show that the two atypical C1 domains are essential for plasma membrane targeting of the protein in intact cells but unnecessary for catalytic activity. We also identify the C-terminal sequence of the protein as essential for membrane binding in a phosphatidic acid-dependent manner. Finally we demonstrate that, in the absence of the calcium binding domain, receptor-dependent translocation of the truncated protein is regulated by phosphorylation of Tyr 335. This functional study provides new insight into the role of the so-called conserved domains of this lipid kinase family and demonstrates the existence of additional domains that confer specific plasma membrane localization to this particular isoform.The transient generation of lipids at the cell membrane by the concerted action of lipases, kinases, and phosphatases is a very effective mechanism for the localization and activation of signaling molecules. The majority of lipid-modifying enzymes are cytosolic proteins that must in turn translocate to the membrane to modify their substrates. Characterization of the mechanism that governs membrane translocation of these proteins is, thus, essential to assess precisely their role in the regulation of cell responses.The diacylglycerol kinases (DGK) 5 are a family of enzymes that phosphorylate diacylglycerol (DAG) to produce phosphatidic acid (PA); this modulates the levels of these two lipids, both of which have recognized second messenger functions. Early experiments showed that DGK activity occupies a central position in phospholipid synthesis; this enzyme attracted additional interest when it was shown to participate in intracellular signaling (1). DGK activity is found in organisms from bacteria to mammals, although the protein identified as a DGK in bacteria is an integral membrane protein (2) and has little structural homology with the DGK characterized in multicellular organisms (3). Ten DGK isoforms have been identified in mammals and grouped into five subtypes based on the presence of various domains in their primary sequences, which define distinct regulatory motifs.Translocation from one subcellular compartment to another appears to be a general theme in the regulation of DGK proteins. Many of the early data regarding DGK activity regulation refer to changes in DGK activity or localization based on enzymatic studies without specifying the isoform concerned (4, 5). Characterization of the DGK isoforms has broadened the concept that these proteins reg...

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Section: Discussionsupporting

confidence: 93%

Role of the Diacylglycerol Kinase α-Conserved Domains in Membrane Targeting in Intact T Cells

Merino¹,

Sanjuán²,

Moraga

et al. 2007

Journal of Biological Chemistry

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“…An attractive possibility was suggested from the observation that DGK acts as a coincidence detector such that its translocation and activation requires both an interaction with, and phosphorylation by, PKC or PKC and occupancy of its own three C-1 sites (van Baal et al, 2005) [however, see also for examples of inhibitory interactions between PKC and DGK]. Although DGK trafficking has not been studied in Xenopus oocytes, it is interesting to note that both PKC and PKC are present (Xiao et al, 2001;Gundersen et al, 2002;Maeno-Hikichi et al, 2003) and the half time for 4␤PMA-mediated enhancement of HCN gating (ϳ5-10 min) is similar to the half time (ϳ6 min) for DGK to migrate to the membrane in A431 cells (van Baal et al, 2005). We thus consider it likely that signaling downstream of DGKs contributes to 4␤PMA regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, translocation of DGK to the plasma membrane requires both occupancy of its C-1 sites by DAG or phorbol ester and an interaction with, and phosphorylation by, PKC or PKC (van Baal et al, 2005). In light of these findings and the important location of DGKs in the generation and regulation of membrane signaling lipids (see supplemental Fig.…”

Section: Activation Of Dgks Contributes To 4␤pma Facilitation Of Hcn mentioning

confidence: 96%

HCN Pacemaker Channel Activation Is Controlled by Acidic Lipids Downstream of Diacylglycerol Kinase and Phospholipase A2

Fogle¹,

Lyashchenko²,

Turbendian³

et al. 2007

J. Neurosci.

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“…In these cascades, phosphorylation of one kinase by the other is mandatory for the activation of the former and differences in terms of kinetics and localization have been reported; these differences depend on whether the cascade is activated via ␤-arrestin or via G proteins (1). The PKC family of isoforms has never been considered up to now as potentially organized into a cascade, although the sequential activation of several isoforms has been observed upon physiological stimulation of living cells (3,19,25,26,31,44,46,47,49,50,53,55). The results of the present study demonstrate the existence of such an organization and unravels a new regulatory mechanism, a coordinated cascade of isoform activation controlling localization at a specific subcellular location.…”

Section: Discussionmentioning

confidence: 99%

A Spatiotemporally Coordinated Cascade of Protein Kinase C Activation Controls Isoform-Selective Translocation

Collazos

Diouf

Guérineau

et al. 2006

Molecular and Cellular Biology

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In pituitary GH3B6 cells, signaling involving the protein kinase C (PKC) multigene family can self-organize into a spatiotemporally coordinated cascade of isoform activation. Indeed, thyrotropin-releasing hormone (TRH) receptor activation sequentially activated green fluorescent protein (GFP)-tagged or endogenous PKC␤1, PKC␣, PKC, and PKC␦, resulting in their accumulation at the entire plasma membrane (PKC␤ and -␦) or selectively at the cell-cell contacts (PKC␣ and -). The duration of activation ranged from 20 s for PKC␣ to 20 min for PKC. PKC␣ and -selective localization was lost in the presence of Gö6976, suggesting that accumulation at cell-cell contacts is dependent on the activity of a conventional PKC. Constitutively active, dominant-negative PKCs and small interfering RNAs showed that PKC␣ localization is controlled by PKC␤1 activity and is calcium independent, while PKC localization is dependent on PKC␣ activity. PKC␦ was independent of the cascade linking PKC␤1, -␣, and -. Furthermore, PKC␣, but not PKC, is involved in the TRH-induced ␤-catenin relocation at cell-cell contacts, suggesting that PKC is not the unique functional effector of the cascade. Thus, TRH receptor activation results in PKC␤1 activation, which in turn initiates a calcium-independent but PKC␤1 activity-dependent sequential translocation of PKC␣ and -. These results challenge the current understanding of PKC signaling and raise the question of a functional dependence between isoforms.Space and time parameters are intimately linked to the biological function of proteins and are pivotal in the organization and functioning of living matter. Particularly important in the case of intracellular signaling networks, this spatiotemporal constraint determines the modalities by which a given protein interacts with its partners in order to exchange information. Efforts are currently being made to translate the experimental evidence of this plasticity into a visualization concept of dynamic signaling networks (4,22). A degree of complexity is added when different isoforms of a protein coexist within the same cell and when they all potentially respond to the same stimulus, which is the case of the protein kinase C (PKC) family.The PKC family is composed of at least 11 isoforms. Several isoforms usually coexist within a given cell type, and each isoform is thought to mediate distinct cellular functions leading to proliferation, differentiation, apoptosis, or secretion. PKC function requires its translocation to a membrane compartment. The current understanding of PKC translocation/ activation has been largely based on the work of Oancea and Meyer (34), who presented conventional PKCs (cPKCs) and novel PKCs (nPKCs) as molecular machines responsible for decoding calcium and/or diacylglycerol (DAG)-mediated signals. Several observations suggest, however, that other, as yet unknown, parameters are involved in the temporal organization of PKC signaling. Indeed, despite similarities in sequence and cofactor regulation by DAG and Ca 2ϩ , the conventional P...

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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

Cited by 70 publications

References 56 publications

Role of the Diacylglycerol Kinase α-Conserved Domains in Membrane Targeting in Intact T Cells

Role of the Diacylglycerol Kinase α-Conserved Domains in Membrane Targeting in Intact T Cells

HCN Pacemaker Channel Activation Is Controlled by Acidic Lipids Downstream of Diacylglycerol Kinase and Phospholipase A2

A Spatiotemporally Coordinated Cascade of Protein Kinase C Activation Controls Isoform-Selective Translocation

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