MAPKs mediate the activation of cytosolic phospholipase A2 by amyloid β(25–35) peptide in bovine retina pericytes

Nicotra, Ambra; Lupo, Gabriella; Giurdanella, Giovanni; Anfuso, Carmelina Daniela; Ragusa, N.; Tirolo, Cataldo; Marchetti, Bianca; Alberghina, Mario

doi:10.1016/j.bbalip.2004.12.017

Cited by 23 publications

(14 citation statements)

References 63 publications

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“…There have been varied reports on the specific kinases responsible for the phosphorylation of cPLA 2 α [14, 16, 33–35]. To correlate the rapid phosphorylation event with transcriptional induction and demonstrate the specificity of p38 MAPK, we examined the effects of inhibitors for p38 MAPK (SB203580 and SB202190), ERK1/2 (PD98059) and JNK (SP600125) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Extensive studies have also implicated cPLA 2 α phosphorylation as an additional cell type- or stimulus-specific regulatory mechanism that can reportedly increase catalytic activity or influence membrane binding affinity associated with transient increases in intracellular calcium [4, 13]. Three relevant residues, Ser505, Ser515, and Ser727, have been reported as phosphorylation sites through the action of either mitogen-activated protein kinases (MAPKs) [14], mitogen-activated protein kinase interacting kinase (MNK1) [11] or calcium/calmodulin-dependent kinase II (CaMKII) [15]. For example, the serine at position 505 on cPLA 2 α has been reported to be phosphorylated by ERK and p38 MAPKs in response to a variety of agonists [16, 17].…”

Section: Introductionmentioning

confidence: 99%

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cPLA2α gene activation by IL-1β is dependent on an upstream kinase pathway, enzymatic activation and downstream 15-lipoxygenase activity: A positive feedback loop

Walters¹,

Bickford²,

Beachy³

et al. 2011

Cellular Signalling

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Cytosolic phospholipase A2α (cPLA2α) is the most widely studied member of the Group IV PLA2 family. The enzyme is Ca2+-dependent with specificity for phospholipid substrates containing arachidonic acid. As the pinnacle of the arachidonic acid pathway, cPLA2α has a primary role in the biosynthesis of a diverse family of eicosanoid metabolites, with potent physiological, inflammatory and pathological consequences. cPLA2α activity is regulated by pro-inflammatory stimuli through pathways involving increased intracellular Ca2+ levels, phosphorylation coupled to increased enzymatic activity and de novo gene transcription. This study addresses the signal transduction pathways for protein phosphorylation and gene induction following IL-1β stimulation in human fetal lung fibroblasts. Our results utilizing both inhibitors and kinase-deficient cells demonstrate that cPLA2α is phosphorylated within 10 min of IL-1β treatment, an event requiring p38 MAPK as well as the upstream kinase, MKK3/MKK6. Inhibition of p38 MAPK also blocks the phosphorylation of a downstream, nuclear kinase, MSK-1. Our results further demonstrate that the activities of both cPLA2α and a downstream lipoxygenase (15-LOX2) are required for IL-1β-dependent induction of cPLA2α mRNA expression. Overall, these data support an MKK3/MKK6→p38 MAPK→MSK-1→cPLA2α→15-LOX2-dependent, positive feedback loop where a protein’s enzymatic activity is required to regulate its own gene induction by a pro-inflammatory stimulus.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

cPLA2α gene activation by IL-1β is dependent on an upstream kinase pathway, enzymatic activation and downstream 15-lipoxygenase activity: A positive feedback loop

Walters¹,

Bickford²,

Beachy³

et al. 2011

Cellular Signalling

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“…Inhibition of cPLA2, both by inhibitors and antisense oligonucleotides, can prevent Abeta-induced cell death in neurons (Kriem et al 2005). Studies with other cell types also demonstrated ability for oligomeric Abeta to activate signaling pathways involving MAPK and cPLA2, which in turn causes mitochondrial dysfunction and cell death (Kriem et al 2005; Nicotra et al 2005; Zhu et al 2006). Squalestatin (as well as simvastatin) was shown to reduce Abeta-induced activation of cPLA2 and PGE2 production and prevented neuronal death (Bate and Williams 2007).…”

Section: Cpla2 In Alzheimer’s Disease (Ad)mentioning

confidence: 99%

Phospholipases A2 and Inflammatory Responses in the Central Nervous System

et al. 2009

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Phospholipases A2 (PLA2s) belong to a superfamily of enzymes responsible for hydrolyzing the sn-2 fatty acids of membrane phospholipids. These enzymes are known to play multiple roles for maintenance of membrane phospholipid homeostasis and for production of a variety of lipid mediators. Over 20 different types of PLA2s are present in the mammalian cells, and in snake and bee venom. Despite their common function in hydrolyzing fatty acids of phospholipids, they are diversely encoded by a number of genes and express proteins that are regulated by different mechanisms. Recent studies have focused on the group IV calcium-dependent cytosolic cPLA2, the group VI calcium-independent iPLA2, and the group II small molecule secretory sPLA2. In the central nervous system (CNS), these PLA2s are distributed among neurons and glial cells. Although the physiological role of these PLA2s in regulating neural cell function has not yet been clearly elucidated, there is increasing evidence for their involvement in receptor signaling and transcriptional pathways that link oxidative events to inflammatory responses that underline many neurodegenerative diseases. Recent studies also reveal an important role of cPLA2 in modulating neuronal excitatory functions, sPLA2 in the inflammatory responses, and iPLA2 with childhood neurologic disorders associated with brain iron accumulation. The goal for this review is to better understand the structure and function of these PLA2s and to highlight specific types of PLA2s and their cross-talk mechanisms in these inflammatory responses under physiological and pathological conditions in the CNS.

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“…There are several reports indicating that cPLA 2 may be a substrate for PKC phosphorylating activity (17,28). Our recent work has also provided in vitro evidence that PKC upstream activates cPLA 2 after stimulation of ECs by oxidized LDL or of pericytes by b-amyloid peptides (29,30). To date, direct evidence for any of the PKC isoforms being involved in the signaling pathway during endothelial cell-pericyte coupling has not been defined.…”

mentioning

confidence: 96%

Endothelial cell-pericyte cocultures induce PLA2 protein expression through activation of PKCα and the MAPK/ERK cascade

Anfuso

Lupo

Romeo

et al. 2007

Journal of Lipid Research

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Little is known about the regulatory mechanisms of endothelial cell (EC) proliferation by retinal pericytes and vice versa. In a model of coculture with bovine retinal pericytes lasting for 24 h, rat brain ECs showed an increase in arachidonic acid (AA) release, whereas Western blot and RT-PCR analyses revealed that ECs activated the protein expression of cytosolic phospholipase A 2 (cPLA 2 ) and its phosphorylated form and calcium-independent intracellular phospholipase A 2 (iPLA 2 ). No activation of the same enzymes was seen in companion pericytes. In ECs, the protein level of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 was also enhanced significantly, a finding not observed in cocultured pericytes. The expression of protein kinase C-a (PKCa) and its phosphorylated form was also enhanced in ECs. Wortmannin, LY294002, and PD98059, used as inhibitors of upstream kinases (the PI3-kinase/Akt/PDK1 or MEK-1 pathway) in cultures, markedly attenuated AA release and the expression of phosphorylated forms of endothelial cPLA 2 , PKCa, and ERK1/2. By confocal microscopy, activation of PKCa in perinuclear regions of ECs grown in coculture as well as strong activation of cPLA 2 in ECs taken from a model of mixed culture were clearly observed. However, no increased expression of both enzymes was found in cocultured pericytes. Our findings indicate that a sequential activation of PKCa contributes to endothelial ERK1/2 and cPLA 2 phosphorylation induced by either soluble factors or direct cell-tocell contact, and that the PKCa-cPLA 2 pathway appears to play a key role in the early phase of EC-pericyte interactions regulating blood retina or blood-brain barrier maturation.-

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MAPKs mediate the activation of cytosolic phospholipase A2 by amyloid β(25–35) peptide in bovine retina pericytes

Cited by 23 publications

References 63 publications

cPLA2α gene activation by IL-1β is dependent on an upstream kinase pathway, enzymatic activation and downstream 15-lipoxygenase activity: A positive feedback loop

cPLA2α gene activation by IL-1β is dependent on an upstream kinase pathway, enzymatic activation and downstream 15-lipoxygenase activity: A positive feedback loop

Phospholipases A2 and Inflammatory Responses in the Central Nervous System

Endothelial cell-pericyte cocultures induce PLA2 protein expression through activation of PKCα and the MAPK/ERK cascade

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