Gα13 mediates activation of the cytosolic phospholipase A2α through fine regulation of ERK phosphorylation

Mariggiò, Stefania; Bavec, Aljoša; Natale, Elena; Zizza, Pasquale; Salmona, Mario; Corda, Daniela; Girolamo, Maria Di

doi:10.1016/j.cellsig.2006.05.003

Cited by 20 publications

(21 citation statements)

References 57 publications

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“…We also determined that the phosphorylation of ERK1/2 results in the production of signaling molecules required for PMN migration (26,85). Again, our evidence demonstrating that S. flexneri induces an ERK1/2-dependent signaling cascade and depends on cPLA 2 for the promotion of PMN transepithelial migration is substantiated by many studies (36,38,40,75,78) and suggests that an increase in cPLA 2 activity is mediated by ERK1/2 (Fig. 9).…”

Section: Discussionsupporting

confidence: 65%

Distinct Isoforms of Phospholipase A₂Mediate the Ability ofSalmonella entericaSerotype Typhimurium andShigella flexneriTo Induce the Transepithelial Migration of Neutrophils

et al. 2008

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Salmonella spp. and Shigella spp. are responsible for millions of cases of enteric disease each year worldwide. While these pathogens have evolved distinct strategies for interacting with the human intestinal epithelium, they both induce significant proinflammatory responses that result in massive transepithelial migration of neutrophils across the intestinal mucosa. It has previously been shown with Salmonella enterica serotype Typhimurium that the process of neutrophil transmigration is mediated in part by the secretion of hepoxilin A 3 (HXA 3 ; 8-hydroxy-11,12-epoxy-eicosatetraenoic acid), a potent neutrophil chemoattractant, from the apical surface of infected model intestinal epithelium. This study confirms that HXA 3 is also secreted in response to infection by Shigella flexneri, that it is produced by a pathway involving 12/15-lipoxygenase (12/15-LOX), and that S. enterica serovar Typhimurium and S. flexneri share certain elements in the mechanism(s) that underlies the otherwise separate signal transduction pathways that are engaged to induce polymorphonuclear leukocyte (PMN) transepithelial migration (protein kinase C and extracellular signal-regulated kinases 1 and 2, respectively). PMN transepithelial migration in response to infection with S. flexneri was dependent on 12/15-LOX activity, the enzyme responsible for the initial metabolism of arachidonic acid to HXA 3 . Probing further into this pathway, we also found that S. enterica serovar Typhimurium and S. flexneri activate different subtypes of phospholipase A 2 , a critical enzyme involved in the liberation of arachidonic acid from cellular membranes. Thus, although S. enterica serovar Typhimurium and S. flexneri utilize different mechanisms for triggering the induction of PMN transepithelial migration, we found that their reliance on 12/15-LOX is conserved, suggesting that enteric pathogens may ultimately stimulate similar pathways for the synthesis and release of HXA 3 .

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Section: Discussionsupporting

confidence: 65%

Distinct Isoforms of Phospholipase A₂Mediate the Ability ofSalmonella entericaSerotype Typhimurium andShigella flexneriTo Induce the Transepithelial Migration of Neutrophils

et al. 2008

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“…RhoA is upstream of not only p38, but also ERK 1/2 . Active RhoA increases ERK 1/2 and p38 activation and consequently cPLA 2 phosphorylation, mainly by ERK 1/2 [59]. Since Rho kinase is the main downstream substrate of RhoA, we hypothesized that Rho kinase regulates cPLA 2 remains unclear and needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Walker

et al. 2016

Mol Neurobiol

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Activation of RhoA/Rho kinase leads to growth cone collapse and neurite retraction. Although RhoA/Rho kinase inhibition has been shown to improve axon regeneration, remyelination and functional recovery, its role in neuronal cell death remains unclear. To determine whether RhoA/Rho kinase played a role in neuronal death after injury, we investigated the relationship between RhoA/Rho kinase and cytosolic phospholipase A 2 (cPLA 2 ), a lipase that mediates inflammation and cell death, using an in vitro neuronal death model and an in vivo contusive spinal cord injury model performed at the 10 th thoracic (T10) vertebral level. We found that coadministration of TNF-α and glutamate induced spinal neuron death, and activation of RhoA, Rho kinase and cPLA 2 . Inhibition of RhoA, Rho kinase and cPLA 2 significantly reduced TNF-α/glutamate-induced cell death by 33%, 52% and 43%, respectively (p < 0.001). Inhibition of RhoA and Rho kinase also significantly down-regulated cPLA 2 activation by 66% and 60%, respectively (p < 0.01). Furthermore, inhibition of RhoA and Rho kinase reduced the release of arachidonic acid, a downstream substrate of cPLA 2 . The immunofluorescence staining showed that ROCK 1 or ROCK 2, two isoforms of Rho kinase, was co-localized with cPLA 2 in neuronal cytoplasm. Interestingly, co-immunoprecipitation (Co-IP) assay showed that ROCK 1 or ROCK 2 , bonded directly with cPLA 2 and phospho-cPLA 2 . When the Rho kinase inhibitor Y27632 was applied in mice with T10 contusion injury, it significantly decreased cPLA 2 activation and expression, and reduced injury-induced apoptosis in the lesion area. Taken together, our results reveal a novel mechanism of RhoA/Rho kinase-mediated neuronal death through regulating cPLA 2 activation.

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“…The role of cytosolic PLA 2 should thus be considered in a more general context that takes into account the levels and activities of the enzymes acting downstream of, and on the products of, PLA 2 , such as the COXs (44). In addition, besides being a substrate of COX, PLA 2 -derived arachidonic acid is also an active molecule per se, as it is involved in induction of apoptosis (45). For example, in mouse and human colon tumors, cPLA 2 is greatly decreased at the mRNA and protein levels compared with normal tissues, whereas levels of COX-2 are increased.…”

Section: Discussionmentioning

confidence: 99%

“…45), 5 and it probably arises from a block of p38 SAPK-dependent phosphatase activity, which results in increased 5 Unpublished results.…”

Section: Discussionmentioning

confidence: 99%

Cytosolic Phospholipase A2α Regulates Cell Growth in RET/PTC-Transformed Thyroid Cells

Mariggiò

Filippi²,

Iurisci³

et al. 2007

Cancer Research

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Modulation of cytosolic phospholipase A 2 (PLA 2 ) expression levels and production of its metabolites have been reported in several tumor types, indicating involvement of arachidonic acid and its derivatives in tumorigenesis. Following our demonstration that the PLA 2 group IV isoform A (PLA 2 IVA) controls TSH-independent growth of normal thyroid (PCCl 3 ) cells, we have investigated the mitogenic role of PLA 2 IVA in rat thyroid cells transformed by the RET/PTC oncogenes (PC-PTC cells). We now report that PLA 2 IVA acts downstream of the RET/PTC oncogenes in a novel pathway controlling RET-dependent cell proliferation. In addition, we show that PLA 2 IVA is in its phosphorylated/active form not only in RET/ PTC-transformed cells and in cells derived from human papillary carcinomas but also in lysates from tumor tissues, thus relating constitutive activation of PLA 2 IVA to RET/PTCdependent tumorigenesis. Moreover, p38 stress-activated protein kinase is the downstream effector of RET/PTC that is responsible for PLA 2 IVA phosphorylation and activity. In summary, our data elucidate a novel mechanism in the control of thyroid tumor cell growth that is induced by the RET/PTC oncogenes and which is distinguishable from that of other oncogenes, such as BRAF. This mechanism is mediated by PLA 2 IVA and should be amenable to targeted pharmacologic intervention.

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Gα13 mediates activation of the cytosolic phospholipase A2α through fine regulation of ERK phosphorylation

Cited by 20 publications

References 57 publications

Distinct Isoforms of Phospholipase A₂Mediate the Ability ofSalmonella entericaSerotype Typhimurium andShigella flexneriTo Induce the Transepithelial Migration of Neutrophils

Distinct Isoforms of Phospholipase A₂Mediate the Ability ofSalmonella entericaSerotype Typhimurium andShigella flexneriTo Induce the Transepithelial Migration of Neutrophils

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Cytosolic Phospholipase A2α Regulates Cell Growth in RET/PTC-Transformed Thyroid Cells

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Gα13 mediates activation of the cytosolic phospholipase A2α through fine regulation of ERK phosphorylation

Cited by 20 publications

References 57 publications

Distinct Isoforms of Phospholipase A2Mediate the Ability ofSalmonella entericaSerotype Typhimurium andShigella flexneriTo Induce the Transepithelial Migration of Neutrophils

Distinct Isoforms of Phospholipase A2Mediate the Ability ofSalmonella entericaSerotype Typhimurium andShigella flexneriTo Induce the Transepithelial Migration of Neutrophils

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Cytosolic Phospholipase A2α Regulates Cell Growth in RET/PTC-Transformed Thyroid Cells

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Distinct Isoforms of Phospholipase A₂Mediate the Ability ofSalmonella entericaSerotype Typhimurium andShigella flexneriTo Induce the Transepithelial Migration of Neutrophils

Distinct Isoforms of Phospholipase A₂Mediate the Ability ofSalmonella entericaSerotype Typhimurium andShigella flexneriTo Induce the Transepithelial Migration of Neutrophils