Neuroregulatory and Neuropathological Actions of the Ether-Phospholipid Platelet-Activating Factor

Kornecki, Elizabeth; Ehrlich, Yigal H.

doi:10.1126/science.3381103

Cited by 241 publications

(90 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among its numerous known roles, PAF can act as an intracellular messenger and can affect neuronal differentiation. [49][50][51] Exposure of neurons to PAF results in growth cone collapse, 52 and inhibition of PAF-AH suppressed migration of cerebellar neurons in vitro. 53,54 Zellweger syndrome patients lack PAF due to disturbed peroxi-some biogenesis 55 and have severe neuronal migration defects.…”

Section: Paf-ahmentioning

confidence: 99%

LIS1—no more no less

2002

View full text Add to dashboard Cite

Section: Paf-ahmentioning

confidence: 99%

LIS1—no more no less

2002

View full text Add to dashboard Cite

“…Interestingly Erk is a candidate for upstream regulators of PAF-induced mitogenesis in lymphocytes (37) and differentiation of neuronal cells (38). PAF reportedly causes phosphorylation of the 42-kDa Erk-2 in human neutrophils (39) and sheep platelets (40).…”

Section: Dual Kinase Activation Of Stat-3 By Pafmentioning

confidence: 99%

Phosphorylation of STAT-3 in Response to Basic Fibroblast Growth Factor Occurs through a Mechanism Involving Platelet-activating Factor, JAK-2, and Src in Human Umbilical Vein Endothelial Cells

Deo¹,

Axelrad²,

Robert³

et al. 2002

Journal of Biological Chemistry

113

View full text Add to dashboard Cite

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid with multiple pathological and physiological effects. We have shown that basic fibroblast growth factor (bFGF) supplementation induces rapid proliferation of human umbilical vein endothelial cells (HUVEC), which is reduced upon removal of bFGF or by bFGF immunoneutralization. The PAF receptor antagonist LAU-8080 inhibited bFGF-stimulated HUVEC proliferation, indicating the involvement of PAF in the bFGF-mediated signaling of HUVEC. Although FGF receptor phosphorylation was not affected by LAU-8080, the bFGF-mediated prolonged phosphorylation, and activation of Erk-1 and -2 were attenuated. Phosphorylation of STAT-3 was observed in the presence of PAF or bFGF, which was attenuated by PAFR antagonists. PAF-induced STAT-3 phosphorylation observed in HUVEC pretreated with either Src inhibitor PP1 or JAK-2 inhibitor AG-490 indicated (i) immediate (1 min) phosphorylation of STAT-3 is dependent on Src, (ii) JAK-2-dependent STAT-3 phosphorylation occurs after the delayed (30 min) PAF exposure, and (iii) prolonged (60 min) STAT-3 phosphorylation may be either through Src and/or JAK-2. Attenuation of the STAT-3 phosphorylation by the PAFR antagonists indicated signaling through the PAF receptor. Taken together, these findings suggest the production of PAF is important for bFGF-mediated signaling and that a dual kinase mechanism is involved in the PAF-mediated signal transduction cascade.is an ether phospholipid second messenger that mediates a number of biological responses, including inflammatory and immune responses, shock, embryogenesis, and cell differentiation (for review, see Ref. 1). PAF is also a potent mediator of pathological angiogenesis associated with tumor expansion and metastasis (2, 3). Hepatocyte growth factor, tumor necrosis factor-␣, and thrombopoietin have been shown to induce angiogenesis through a mechanism involving PAF (4, 5). Many cells produce PAF, including monocytes, endothelial cells, neutrophils, and lymphocytes, and these cell types can themselves become targets of PAF bioactions (6). PAF acts through a specific Gprotein-linked receptor containing seven ␣-helical domains that span the plasma membrane (7) and has been localized to the plasmalemma (8) and a large endosomal compartment on human umbilical vein endothelial cells (HUVEC) (9). PAF also up-regulates the expression of its own receptor in several cell types including human alveolar macrophages (10) and rat epithelial cells (11), thus potentially providing a positive feedback loop for PAF action.Of the 20 members of the FGF family of growth factors, only acidic FGF and basic FGF (bFGF) have been shown to regulate proliferation and migration of capillary endothelial cells (for review, see Refs. 12 and 13). Although bFGF does not contain a traditional signal sequence, it is now clear that it is secreted via a tightly regulated non-conventional secretory pathway and is localized in the basement membrane and extracellular matrix of numerous tissues (14). bFGF binds t...

show abstract

“…3) PAFR-independent cell death can be inhibited by two PAF antagonists: the gingkolide BN 52021 and the fungal derivative Apoptotic PAF Signal Transduction in the Absence of PAFR-To provide mechanistic insight into how PAF transduces cell death in the absence of PAFR, we followed the internalization and metabolic fate of Bodipy fluorophore-conjugated PAF in PAF-sensitive cells (11,43). PC12 cells express all of the components of both cytosolic PAF-AH enzymes (I and II) but not plasma PAF-AH or PAFR.…”

Section: Cytosolic Paf-ahs Can Be Targeted Pharmacologically To Promomentioning

confidence: 99%

Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit

Bonin¹,

Ryan²,

Migahed³

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Platelet-activating factor (PAF) is an important mediator of cell loss following diverse pathophysiological challenges, but the manner in which PAF transduces death is not clear. Both PAF receptor-dependent and -independent pathways are implicated. In this study, we show that extracellular PAF can be internalized through PAF receptor-independent mechanisms and can initiate caspase-3-dependent apoptosis when cytosolic concentrations are elevated by ϳ15 pM/cell for 60 min. Reducing cytosolic PAF to less than 10 pM/cell terminates apoptotic signaling. By pharmacological inhibition of PAF acetylhydrolase I and II (PAF-AH) activity and down-regulation of PAF-AH I catalytic subunits by RNA interference, we show that the PAF receptor-independent death pathway is regulated by PAF-AH I and, to a lesser extent, by PAF-AH II. Moreover, the anti-apoptotic actions of PAF-AH I are subunit-specific. PAF-AH I ␣ 1 regulates intracellular PAF concentrations under normal physiological conditions, but expression is not sufficient to reduce an acute rise in intracellular PAF levels. PAF-AH I ␣ 2 expression is induced when cells are deprived of serum or exposed to apoptogenic PAF concentrations limiting the duration of pathological cytosolic PAF accumulation. To block PAF receptor-independent death pathway, we screened a panel of PAF antagonists (CV-3988, CV-6209, BN 52021, and FR 49175). BN 52021 and FR 49175 accelerated PAF hydrolysis and inhibited PAF-mediated caspase 3 activation. Both antagonists act indirectly to promote PAF-AH I ␣ 2 homodimer activity by reducing PAF-AH I ␣ 1 expression. These findings identify PAF-AH I ␣ 2 as a potent antiapoptotic protein and describe a new means of pharmacologically targeting PAF-AH I to inhibit PAF-mediated cell death.Platelet-activating factor (PAF, 1 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a key mediator of neuronal death in ischemia, encephalitis, epileptic seizure, meningitis, and human immunodeficiency virus-1 dementia in vivo and participates in etoposide-, prion-, and ␤-amyloid-induced cell death in vitro (1-7). In the periphery, pathological increases in PAF concentrations underlie cytotoxicity in chronic inflammatory dermatoses and lethality in systemic anaphylaxis (8, 9). Although the majority of PAF effects are understood to be transduced by its G-protein-coupled receptor (PAFR) (10), PAFR signaling has been shown to be both pro-and anti-apoptotic. Ectopic PAFR expression exacerbates cell death induced by etoposide and mitomycin C but protects cells from tumor necrosis factor ␣, TRAIL, and extracellular PAF (6,7,11,12). These opposing effects likely depend upon the relative ratio of NF-B-dependent pro-and anti-apoptotic gene products elicited in different cell types in response to the combination of an external apoptotic inducer and PAF (6).Accumulating evidence points to additional PAF signaling pathways transduced independently of PAFR (11, 13-17). PAFR-negative cells undergo apoptosis when extracellular PAF concentrations reach 100 nM and necrosis when PAF levels e...

show abstract

Neuroregulatory and Neuropathological Actions of the Ether-Phospholipid Platelet-Activating Factor

Cited by 241 publications

References 20 publications

LIS1—no more no less

LIS1—no more no less

Phosphorylation of STAT-3 in Response to Basic Fibroblast Growth Factor Occurs through a Mechanism Involving Platelet-activating Factor, JAK-2, and Src in Human Umbilical Vein Endothelial Cells

Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit

Contact Info

Product

Resources

About