Phospholipid Scramblase Activation Pathways in Lymphocytes

Williamson, Patrick; Christie, Allison J.; Kohlin, Torvald; Schlegel, Robert; Comfurius, Paul; Harmsma, Marjan; Zwaal, R.F.A.; Bevers, Edouard M.

doi:10.1021/bi001929z

Cited by 108 publications

(132 citation statements)

References 26 publications

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“…In situ analysis was conducted as previously described (28). Onzin cDNA from the IMAGE clone was 35 S labeled for sense and antisense transcripts using Maxiscript kit (Ambion). Frozen tissue sections were prepared as described previously (28).…”

Section: Methodsmentioning

confidence: 99%

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Impaired Host Defense in Mice Lacking ONZIN

Ledford

Kovářová

Koller

2007

The Journal of Immunology

101

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ONZIN is a small, cysteine-rich peptide of unique structure that is conserved in all vertebrates examined to date. We show that ONZIN is expressed at high levels in epithelial cells of the intestinal tract, the lung, and in cells of the immune system including macrophages and granulocytes. Because this pattern of expression is suggestive of a role in innate immune function, we have generated mice lacking this protein and examined their ability to respond to challenge with infectious agents. Onzin−/− mice show a heightened innate immune response after induction of acute peritonitis with Klebsiella pneumoniae. This increased response is consistent with an increased bacterial burden in the Onzin−/− mice. Ex vivo studies show that, whereas phagocytosis is not altered in Onzin−/− neutrophils, phagocytes lacking this protein kill bacteria less effectively. This result identifies ONZIN as a novel class of intracellular protein required for optimal function of the neutrophils after uptake of bacteria.

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Section: Methodsmentioning

confidence: 99%

“…allophycocyanin-labeled annexin V (BD Pharmingen) was used to detect the appearance of phosphatidylserine (PS) at the cell surface as described previously (35). Briefly, 2 ϫ 10 5 cells in buffer (10 mM HEPES, 150 mM NaCl, 2.5 mM CaCl 2 , (pH7.4)) were labeled with annexin V and stained with 7-AAD vital dye.…”

Section: Cell Viability and Flow Cytometrymentioning

confidence: 99%

Impaired Host Defense in Mice Lacking ONZIN

Ledford

Kovářová

Koller

2007

The Journal of Immunology

101

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“…64,65 To identify the scramblases responsible for apoptotic PtdSer exposure, we again performed expression cloning using the Ba/F3-PS19 cDNA library. Assuming that scramblases, like channels, should be large membrane proteins, we first screened a library of long cDNAs (42.5 kb) and obtained the TMEM16F cDNA, encoding 911 amino acids.…”

Section: Caspase-dependent Scramblasesmentioning

confidence: 99%

Exposure of phosphatidylserine on the cell surface

et al. 2016

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“…In quiescent platelets, PS is maintained in the inner leaflet of the plasma membrane. Stimulation of platelets subsequently switches on the activity of a Ca 2ϩ -dependent phospholipid scramblase (22,23), resulting in surface exposure of negatively charged PS, required for the binding of coagulation factor complexes (24). PKC isoforms variably regulate platelet Ca 2ϩ signals and have influences on PS exposure (19,25,26).…”

mentioning

confidence: 99%

Critical Role for CD38-mediated Ca2+ Signaling in Thrombin-induced Procoagulant Activity of Mouse Platelets and Hemostasis

Mushtaq¹,

Nam²,

Kim

2011

Journal of Biological Chemistry

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CD38, a multifunctional enzyme that catalyzes the synthesis of intracellular Ca 2؉ messengers, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), is known to be expressed on platelets. However, the role of CD38 in platelets remains unclear. Our present results show that treatment of platelets with thrombin results in a rapid and sustained Ca 2؉ signal, resulting from a coordinated interplay of Ca 2؉ -mobilizing messengers, inositol 1,4,5-trisphosphate, cADPR, and NAADP. By dissecting the signaling pathway using various agents, we delineated that cADPR and NAADP are sequentially produced through CD38 internalization by protein kinase C via myosin heavy chain IIA following phospholipase C activation in thrombin-induced platelets. An inositol 1,4,5-trisphosphate receptor antagonist blocked the thrombin-induced formation of cADPR and NAADP as well as Ca 2؉ signals. An indispensable response of platelets relying on cytosolic calcium is the surface exposure of phosphatidylserine (PS), which implicates platelet procoagulant activity. Scrutinizing this parameter reveals that CD38 ؉/؉ platelets fully express PS on the surface when stimulated with thrombin, whereas this response was decreased on CD38 ؊/؊ platelets. Similarly, PS exposure and Ca 2؉ signals were attenuated when platelets were incubated with 8-bromo-cADPR, bafilomycin A1, and a PKC inhibitor. Furthermore, in vivo, CD38-deficient mice exhibited longer bleeding times and unstable formation of thrombus than wild type mice. These results demonstrate that CD38 plays an essential role in thrombin-induced procoagulant activity of platelets and hemostasis via Ca 2؉ signaling mediated by its products, cADPR and NAADP.

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Phospholipid Scramblase Activation Pathways in Lymphocytes

Cited by 108 publications

References 26 publications

Impaired Host Defense in Mice Lacking ONZIN

Impaired Host Defense in Mice Lacking ONZIN

Exposure of phosphatidylserine on the cell surface

Critical Role for CD38-mediated Ca2+ Signaling in Thrombin-induced Procoagulant Activity of Mouse Platelets and Hemostasis

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