A Dual Role for Diacylglycerol Kinase Generated Phosphatidic Acid in Autoantibody-Induced Neutrophil Exocytosis

Holden, Neil; Savage, Caroline O. S.; Young, Stephen P.; Wakelam, Michael J.O.; Harper, Lorraine; Williams, Julie M.

doi:10.2119/molmed.2011.00028

Cited by 13 publications

(18 citation statements)

References 63 publications

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“…This delay means that PA could play a facilitory role in sperm-egg fusion in addition to releasing most [Ca] i . Our demonstration that PA mass is elevated during the period of sperm-egg fusion (estimated at ~1 minute after insemination)(Stith et al, 1993) and cortical granule-plasma membrane fusion (the time of the [Ca] i wave; ~4 to 6 minutes postinsemination)(Stith et al, 1994) is not surprising in light of past studies linking PLD, PA and exocytosis in neutrophil, neuroendocrine, neurons, mast cells, pancreatic β cells and adipocytes (Chasserot-Golaz et al, 2010; Cockcroft et al, 2002; Holden et al, 2011; Su and Frohman, 2011; Vitale, 2010; Vitale et al, 2002; Zeniou-Meyer et al, 2008; Zeniou-Meyer et al, 2007). …”

Section: Discussionmentioning

confidence: 72%

Activation of Src and release of intracellular calcium by phosphatidic acid during Xenopus laevis fertilization

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Holland

et al. 2014

Developmental Biology

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We report a new step in the fertilization in Xenopus laevis which has been found to involve activation of Src tyrosine kinase to stimulate phospholipase C-γ (PLC- γ) which increases inositol 1,4,5-trisphosphate (IP3) to release intracellular calcium ([Ca]i). Molecular species analysis and mass measurements suggested that sperm activate phospholipase D (PLD) to elevate phosphatidic acid (PA). We now report that PA mass increased 2.7 fold by 1 minute after insemination and inhibition of PA production by two methods inhibited activation of Src and PLCγ, increased [Ca]i and other fertilization events. As compared to 14 other lipids, PA strongly bound Xenopus Src but not PLCγ. Addition of synthetic PA activated egg Src (an action requiring intact lipid rafts) and PLCγ as well as doubling the amount of PLCγ in rafts. In the absence of elevated [Ca]i, PA addition elevated IP3 mass to levels equivalent to that induced by sperm (but twice that achieved by calcium ionophore). Finally, PA induced [Ca]i release that was blocked by an IP3 receptor inhibitor. As only PLD1b message was detected, and Western blotting did not detect PLD2, we suggest that sperm activate PLD1b to elevate PA which then binds to and activates Src leading to PLCγ stimulation, IP3 elevation and [Ca]i release. Due to these and other studies, PA may also play a role in membrane fusion events such as sperm-egg fusion, cortical granule exocytosis, the elevation of phosphatidylinositol 4,5-bisphosphate and the large, late increase in sn 1,2-diacylglycerol in fertilization.

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Section: Discussionmentioning

confidence: 72%

Activation of Src and release of intracellular calcium by phosphatidic acid during Xenopus laevis fertilization

Bates

Fees

Holland

et al. 2014

Developmental Biology

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“…Moreover the exclusive localization of PIP 2 in the apical membrane (Bryant and Mostov, 2008;Gá lvez-Santisteban et al, 2012) should limit the chance for unexpected effects of DGK inhibitors. Interestingly, this target has been recently proposed to treat inflammation, coagulation, and cancer (Holden et al, 2011;Marumo et al, 2012;Filigheddu et al, 2011) with no reported toxicity.…”

Section: Discussionmentioning

confidence: 99%

High-Content siRNA Screen Reveals Global ENaC Regulators and Potential Cystic Fibrosis Therapy Targets

Almaça

Faria

Sousa

et al. 2013

Cell

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Dysfunction of ENaC, the epithelial sodium channel that regulates salt and water reabsorption in epithelia, causes several human diseases, including cystic fibrosis (CF). To develop a global understanding of molecular regulators of ENaC traffic/function and to identify of candidate CF drug targets, we performed a large-scale screen combining high-content live-cell microscopy and siRNAs in human airway epithelial cells. Screening over 6,000 genes identified over 1,500 candidates, evenly divided between channel inhibitors and activators. Genes in the phosphatidylinositol pathway were enriched on the primary candidate list, and these, along with other ENaC activators, were examined further with secondary siRNA validation. Subsequent detailed investigation revealed ciliary neurotrophic factor receptor (CNTFR) as an ENaC modulator and showed that inhibition of (diacylglycerol kinase, iota) DGKι, a protein involved in PiP2 metabolism, downgrades ENaC activity, leading to normalization of both Na+ and fluid absorption in CF airways to non-CF levels in primary human lung cells from CF patients.

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“…Phosphatidic acid, LPA and DAG are involved in many membrane fusion and membrane fission events, such as fission of Golgi membranes , fission during endocytic transport , vacuole fission and fusion , mitochondrial dynamics , exocytosis , vesicle‐vesicle fusion , myoblast fusion , osteoclast fusion , membrane fusion during sporulation , membrane fusion during fertilization . Fusion of PA‐containing vesicles was studied in Refs .…”

Section: The Role Of Pa In Membrane Fusion and Membrane Fissionmentioning

confidence: 99%

Phosphatidic acid in membrane rearrangements

et al. 2019

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Phosphatidic acid (PA) is the simplest cellular glycerophospholipid characterized by unique biophysical properties: a small headgroup; negative charge; and a phosphomonoester group. Upon interaction with lysine or arginine, PA charge increases from −1 to −2 and this change stabilizes protein–lipid interactions. The biochemical properties of PA also allow interactions with lipids in several subcellular compartments. Based on this feature, PA is involved in the regulation and amplification of many cellular signalling pathways and functions, as well as in membrane rearrangements. Thereby, PA can influence membrane fusion and fission through four main mechanisms: it is a substrate for enzymes producing lipids (lysophosphatidic acid and diacylglycerol) that are involved in fission or fusion; it contributes to membrane rearrangements by generating negative membrane curvature; it interacts with proteins required for membrane fusion and fission; and it activates enzymes whose products are involved in membrane rearrangements. Here, we discuss the biophysical properties of PA in the context of the above four roles of PA in membrane fusion and fission.

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A Dual Role for Diacylglycerol Kinase Generated Phosphatidic Acid in Autoantibody-Induced Neutrophil Exocytosis

Cited by 13 publications

References 63 publications

Activation of Src and release of intracellular calcium by phosphatidic acid during Xenopus laevis fertilization

Activation of Src and release of intracellular calcium by phosphatidic acid during Xenopus laevis fertilization

High-Content siRNA Screen Reveals Global ENaC Regulators and Potential Cystic Fibrosis Therapy Targets

Phosphatidic acid in membrane rearrangements

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