Molecular Mechanisms of <i>N</i>-Formyl-Methionyl-Leucyl-Phenylalanine-Induced Superoxide Generation and Degranulation in Mouse Neutrophils: Phospholipase D Is Dispensable

Sato, Takanobu; Hongu, Tsunaki; Sakamoto, Megumi; Funakoshi, Yuji; Kanaho, Yasunori

doi:10.1128/mcb.00869-12

Cited by 56 publications

(45 citation statements)

References 75 publications

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“…However, the involvement of PLD in these events became uncertain when it was shown that a newly developed PLD-specific inhibitor (FIPI) did not affect many of the biological processes that are inhibited by 1-butanol (19,20). Moreover, a recent study has also shown that several ethanol (a two-carbon primary alcohol)-sensitive events were not observed when more reliable techniques, such as a genetic deletion of PLD, were employed (21). Consistent with the concerns raised by these studies, we found that, although FIPI could block agonist-induced changes in PLD activity, it did not prevent the mechanically induced increase in PA or mTOR signaling.…”

Section: Discussionmentioning

confidence: 99%

The Role of Diacylglycerol Kinase ζ and Phosphatidic Acid in the Mechanical Activation of Mammalian Target of Rapamycin (mTOR) Signaling and Skeletal Muscle Hypertrophy

You¹,

Lincoln²,

Kim³

et al. 2014

Journal of Biological Chemistry

138

130

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Background: Diacylglycerol kinases (DGKs) synthesize phosphatidic acid (PA), and PA can activate growth-regulatory mTOR signaling. Results:The isoform of DGK is necessary for a mechanically induced increase in PA-mTOR signaling, and overexpression of DGK induces skeletal muscle hypertrophy. Conclusion: PA synthesized by DGK regulates the mechanical activation of mTOR signaling and hypertrophy. Significance: DGK is a potential target for treating muscle atrophy/wasting.

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Section: Discussionmentioning

confidence: 99%

The Role of Diacylglycerol Kinase ζ and Phosphatidic Acid in the Mechanical Activation of Mammalian Target of Rapamycin (mTOR) Signaling and Skeletal Muscle Hypertrophy

You¹,

Lincoln²,

Kim³

et al. 2014

Journal of Biological Chemistry

138

130

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“…DOCK5-deficient (D5 Ϫ/Ϫ ) mice, PLD1-deficient (PLD1 Ϫ/Ϫ ) mice, and PLD2-deficient (PLD2 Ϫ/Ϫ ) mice have been described elsewhere (22,31,32). Mice homozygous for DOCK1 alleles containing floxed exon 1 (DOCK1 flox/flox ) will be described elsewhere.…”

Section: Methodsmentioning

confidence: 99%

Phosphatidic Acid-dependent Recruitment and Function of the Rac Activator DOCK1 during Dorsal Ruffle Formation

Sanematsu

Nishikimi

Watanabe

et al. 2013

Journal of Biological Chemistry

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Background: DOCK1 is an atypical Rac activator. Results: Activation of the PDGF receptor induces DOCK1 translocation to the dorsal ruffles through association with phosphatidic acid. Blocking of this interaction impairs dorsal, but not peripheral, ruffle formation. Conclusion: Phosphatidic acid acts as a lipid anchor for DOCK1 during dorsal ruffle formation. Significance: A novel regulatory mechanism for dorsal ruffle formation was identified.

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“…14,15 In recent years, however, PLD inhibition has become achievable using small molecule inhibitors. 16 An inhibitor screen identified 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) as a potent and reversible inhibitor of both PLD isoforms, with a half-life of 5.5 hours in vivo and moderate bioavailability.…”

mentioning

confidence: 99%

Pharmacological Inhibition of Phospholipase D Protects Mice From Occlusive Thrombus Formation and Ischemic Stroke—Brief Report

Stegner

Thielmann

Kraft

et al. 2013

ATVB

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Objective-We recently showed that mice lacking the lipid signaling enzyme phospholipase (PL) D1 or both PLD isoforms (PLD1 and PLD2) were protected from pathological thrombus formation and ischemic stroke, whereas hemostasis was not impaired in these animals. We sought to assess whether pharmacological inhibition of PLD activity affects hemostasis, thrombosis, and thrombo-inflammatory brain infarction in mice. Approach and Results-Treatment of platelets with the reversible, small molecule PLD inhibitor, 5-fluoro-2-indolyl deschlorohalopemide (FIPI), led to a specific blockade of PLD activity that was associated with reduced α-granule release and integrin activation. Mice that received FIPI at a dose of 3 mg/kg displayed reduced occlusive thrombus formation upon chemical injury of carotid arteries or mesenterial arterioles. Similarly, FIPI-treated mice had smaller infarct sizes and significantly better motor and neurological function 24 hours after transient middle cerebral artery occlusion. This protective effect was not associated with major intracerebral hemorrhage or prolonged tail bleeding times. Conclusions-These results provide the first evidence that pharmacological PLD inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and ischemic stroke. 11,23 Here, we show that pharmacological inhibition of PLD activity with FIPI specifically reduced PLDdependent α-granule release and integrin activation resulting in decreased thrombosis and infarct progression during acute stroke in mice without affecting hemostasis. Materials And MethodsMaterials and Methods are available in the online-only Supplement. Results FIPI Treatment Abolishes PLD Activity and Leads to Defective Integrin Activation and α-Granule ReleaseIt has been shown that platelets of Pld1−/− mice display defective integrin activation and α-granule release on platelet stimulation with intermediate concentration of thrombin.11 To assess whether the small, reversible PLD inhibitor FIPI specifically inhibits PLD and whether this leads to the same effects as observed in the PLD1/2 double-deficient mice, we analyzed PLD activity and platelet activation on FIPI treatment. Although platelet stimulation with thrombin triggered PLD activity in vehicle-treated platelets, FIPI dose-dependently inhibited PLD activity ( Figure 1A). In subsequent in vitro experiments we chose to use 100 nmol/L FIPI because this was the lowest concentration that abolished PLD activity, consistent with results for other cell types.14 Treatment of platelets with this concentration of FIPI did not alter glycoprotein expression on the platelet surface (data not shown). Integrin activation and P-selectin exposure, as a measurement for α-granule release, were analyzed flow cytometrically in vehicle-and FIPI-treated wild-type and Pld1−/− mice to test for potential off-target effects created by FIPI. The results revealed decreased integrin activation and α-granule release in FIPI-treated platelets upon stimulation with an intermediate concentration (3 mU/mL) of...

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Molecular Mechanisms of N-Formyl-Methionyl-Leucyl-Phenylalanine-Induced Superoxide Generation and Degranulation in Mouse Neutrophils: Phospholipase D Is Dispensable

Cited by 56 publications

References 75 publications

The Role of Diacylglycerol Kinase ζ and Phosphatidic Acid in the Mechanical Activation of Mammalian Target of Rapamycin (mTOR) Signaling and Skeletal Muscle Hypertrophy

The Role of Diacylglycerol Kinase ζ and Phosphatidic Acid in the Mechanical Activation of Mammalian Target of Rapamycin (mTOR) Signaling and Skeletal Muscle Hypertrophy

Phosphatidic Acid-dependent Recruitment and Function of the Rac Activator DOCK1 during Dorsal Ruffle Formation

Pharmacological Inhibition of Phospholipase D Protects Mice From Occlusive Thrombus Formation and Ischemic Stroke—Brief Report

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