Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions

Mérida, Isabel; Andrada, Elena; Gharbi, Severine; Ávila-Flores, Antonia

doi:10.1126/scisignal.aaa0974

Cited by 62 publications

(81 citation statements)

References 103 publications

(135 reference statements)

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“…In this pathway Raf-1 phosphorylates and activates MAP/ERK kinase (MEK)1/2, which in turn phosphorylate and activate ERK1/2. ERK has more than 150 known substrates [9,12], which mediate many of the pleiotropic functions of this pathway [13,14]. Raf-1 regulation is complex and is still insufficiently understood.…”

Section: Introductionmentioning

confidence: 99%

PDE8 controls CD4+ T cell motility through the PDE8A-Raf-1 kinase signaling complex

Basole¹,

Nguyen²,

Lamothe³

et al. 2017

Cellular Signalling

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The levels of cAMP are regulated by phosphodiesterase enzymes (PDEs), which are targets for the treatment of inflammatory disorders. We have previously shown that PDE8 regulates T cell motility. Here, for the first time, we report that PDE8A exerts part of its control of T cell function through the V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase signaling pathway. To examine T cell motility under physiologic conditions, we analyzed T cell interactions with endothelial cells and ligands in flow assays. The highly PDE8-selective enzymatic inhibitor PF-04957325 suppresses adhesion of in vivo myelin oligodendrocyte glycoprotein (MOG) activated inflammatory CD4 + T effector (Teff) cells to brain endothelial cells under shear stress. Recently, PDE8A was shown to associate with Raf-1 creating a compartment of low cAMP levels around Raf-1 thereby protecting it from protein kinase A (PKA) mediated inhibitory phosphorylation. To test the function of this complex in Teff cells, we used a cell permeable peptide that selectively disrupts the PDE8A-Raf-1 interaction. The disruptor peptide inhibits the Teff-endothelial cell interaction more potently than the enzymatic inhibitor. Furthermore, the LFA-1/ICAM-1 interaction was identified as a target of disruptor peptide mediated reduction of adhesion, spreading and locomotion of Teff cells under flow. Mechanistically, we observed that disruption of the PDE8A-Raf-1 complex profoundly alters Raf-1 signaling in Teff cells. Collectively, our studies demonstrate that PDE8A inhibition by enzymatic inhibitors or PDE8A-Raf-1 kinase complex disruptors decreases Teff cell adhesion and migration under flow, and represents a novel approach to target T cells in inflammation.Keywords: PDE8 CD4 + T cells Integrins Autoimmunity T cell motility, Inflammation 2 IntroductionLigand binding to Gs-coupled receptors leads to the generation of the second messenger cAMP following activation of the enzyme adenylyl cyclase. Stimulation of the T cell antigen receptor (TCR) also leads to elevation of cAMP which is known to inhibit T cell proximal signaling, IL-2 production and T cell proliferation [1,2]. cAMP exerts these inhibitory effects in T cells through cAMP dependent protein kinase (PKA) which blocks the mitogen-activated protein kinase (MAPK) and nuclear factor of activated T cells (NFAT) dependent signaling pathways [3]. The inhibitory action of cAMP is eliminated through the action of phosphodiesterase (PDE) enzymes that hydrolyze cAMP. PDEs 3B, 4A, 4B, 4D, 7A1, 7A3 and 8A1 are the isoforms expressed in T cells [4][5][6][7][8]. V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) is an upstream regulator of the MAPK-extracellular signal-regulated kinase (ERK)1/2 module, which controls many fundamental biological processes, including T cell proliferation, survival and adhesion [9][10][11][12]. In this pathway Raf-1 phosphorylates and activates MAP/ERK kinase (MEK)1/2, which in turn phosphorylate and activate ERK1/2. ERK has more than 150 known substrates [9,12], which med...

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Section: Introductionmentioning

confidence: 99%

PDE8 controls CD4+ T cell motility through the PDE8A-Raf-1 kinase signaling complex

Basole¹,

Nguyen²,

Lamothe³

et al. 2017

Cellular Signalling

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“…DAG kinases (DGKs) are a family of 10 enzymes that catalyze phosphorylation of DAG into phosphatidic acid (PA) and thus inhibit DAG-mediated signaling in mammals [10, 22]. DGKα and ζ are the major isoforms expressed in T cells [23–25].…”

Section: Introductionmentioning

confidence: 99%

Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation

et al. 2016

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Signals from the T-cell receptor (TCR) and γ-chain cytokine receptors play crucial roles in initiating activation and effector/memory differentiation of CD8 T-cells. We report here that simultaneous deletion of both diacylglycerol kinase (DGK) α and ζ (DKO) severely impaired expansion of CD8 effector T cells and formation of memory CD8 T-cells after Listeria monocytogenes infection. Moreover, ablation of both DGKα and ζ in preformed memory CD8 T-cells triggered death and impaired homeostatic proliferation of these cells. DKO CD8 T-cells were impaired in priming due to decreased expression of chemokine receptors and migration to the draining lymph nodes. Moreover, DKO CD8 T-cells were unexpectedly defective in NFκB-mediated miR-155 transcript, leading to excessive SOCS1 expression and impaired γ-chain cytokine signaling. Our data identified a DGK-NFκB-miR-155-SOCS1 axis that bridges TCR and γ-chain cytokine signaling for robust CD8 T-cell primary and memory responses to bacterial infection.

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“…Effects of DGKα on oncogenes can also be indirect, with one example being the regulation of HIF-1α via modulating the interaction of the degradative von Hippel Lindau (vHL) protein with HIF-1α; the role of PA in this interaction is not established (12, 18). DGKα effects in cancer might also stem from affecting DAG levels (19)—though this seems less likely given the high concentration of DAG in the membrane, the numerous DGK family members, and the existence of other DAG-modulating pathways; DAG can be generated by lipase action on triacylglycerols, phospholipase action on phospholipids, phosphatase action on PA, and acyltransferase action on monoacylglycerols (20). …”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer

Purow

2015

Clinical Cancer Research

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Lipid kinases have largely been neglected as targets in cancer, and an increasing number of reports suggest diacylglycerol kinase alpha (DGKα) may be one with promising therapeutic potential. DGKα is one of ten DGK family members that convert diacylglycerol (DAG) to phosphatidic acid (PA), and both DAG and PA are critical lipid second messengers in the plasma membrane. A host of important oncogenic proteins and pathways affect cancer cells in part through DGKα, including the c-Met and VEGF receptors. Others partially mediate the effects of DGKα inhibition in cancer, such as mTOR and HIF-1α. DGKα inhibition can directly impair cancer cell viability, inhibits angiogenesis, and notably may also boost T cell activation and enhance cancer immunotherapies. While two structurally similar inhibitors of DGKα were established decades ago, they have seen minimal in vivo usage and it is unlikely that either of these older DGKα inhibitors will have utility for cancer. An abandoned compound that also inhibits serotonin receptors may have more translational potential as a DGKα inhibitor, but more potent and specific DGKα inhibitors are sorely needed. Other DGK family members may also provide therapeutic targets in cancer, but require further investigation.

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Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions

Cited by 62 publications

References 103 publications

PDE8 controls CD4+ T cell motility through the PDE8A-Raf-1 kinase signaling complex

PDE8 controls CD4+ T cell motility through the PDE8A-Raf-1 kinase signaling complex

Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation

Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer

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