Identification of Prostaglandin E2 Receptor Subtype 2 As a Receptor Activated by OxPAPC

Li, Rongsong; Mouillesseaux, Kevin P.; Montoya, Dennis; Cruz, Daniel; Gharavi, Nima M.; Dun, Martin; Koroniak, Lukasz; Berliner, Judith A.

doi:10.1161/01.res.0000207394.39249.fc

Cited by 103 publications

(109 citation statements)

References 37 publications

(52 reference statements)

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“…Of relevance, LDL-derived oxidized phospholipids have been shown to induce formation of the second messenger cAMP (Cole et al, 2003). More recently, the PGE 2 receptor EP2 has been shown to specifically bind a LDL-derived oxidized phospholipid (Li et al, 2006). We have demonstrated that an EP2 antagonist was unable to antagonize the activity of PCERA-1 in macrophages ).…”

Section: Evidence For a Pcera-1 Receptormentioning

confidence: 79%

Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Levi

Meijler

Gómez-Muñoz

et al. 2010

Molecular and Cellular Endocrinology

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. Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1). Molecular and Cellular Endocrinology, Elsevier, 2009, 314 (2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 Ceramide-1-phosphate (C1P) is known as a second messenger regulating a multitude of processes including cell growth, apoptosis and inflammation. Exciting recent findings now suggest that C1P can stimulate macrophages migration in an extra-cellular manner via a G protein-coupled receptor (GPCR). Interestingly, a synthetic C1P analog, named phospho-ceramide analogue-1 (PCERA-1), was recently described as a potent in-vivo anti-inflammatory agent, and was suggested to act on macrophages in an extra-cellular manner via a GPCR. Here we summarize and compare the receptor-mediated as well as receptor-independent activities of natural C1P and its synthetic analog. We also provide experimental data in support of distinct C1P and PCERA-1 receptors.Page 3 of 20A c c e p t e d M a n u s c r i p t 3 IntroductionIt is well-established that sphingolipids are crucial metabolites for controlling cell and tissue homeostasis. In particular, ceramides induce cell cycle arrest and are potent inducers of apoptosis. Also, ceramides play crucial roles in the regulation of cell differentiation, and inflammation (Hannun et al., 1986;Hannun, 1994;Hannun and Obeid, 1995;Hannun, 1996;Hannun and Obeid, 2002;Kolesnick, 1994;Kolesnick, 1987;Kolesnick and Hemer, 1990;Kolesnick et al., 2000;Merrill and Jones, 1990;Merrill et al., 1997;Merrill, 2002;Spiegel and Merrill, 1996).Ceramides are generated either by de novo synthesis, or by the action of different sphingomyelinases (SMases), whose activities, enzymology, and compartmentalization have been thoroughly reviewed by others (Cremesti et al., 2002;Goni and Alonso, 2002;Kolesnick et al., 2000). A major metabolite of ceramide is ceramide-1-phosphate (C1P, Fig. 1), which is generated through direct phosphorylation of ceramide by ceramide kinase (CERK) (Bajjalieh et al., 1989;Kolesnick and Hemer, 1990). This enzyme was first shown to be confined to the microsomal fraction, but its location in the cytosol has also been reported (Mitsutake et al., 2004). Recently, Chalfant and co-workers demonstrated that CERK utilizes ceramide transported to the trans-Golgi apparatus by the ceramide transport protein (CERT). Of note, down-regulation of CERT by RNA interference resulted in strong inhibition of newly synthesized C1P, suggesting that CERT plays a critical role in C1P formation . However, this observation contrasts with that of Bornancin and...

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Section: Evidence For a Pcera-1 Receptormentioning

confidence: 79%

Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Levi

Meijler

Gómez-Muñoz

et al. 2010

Molecular and Cellular Endocrinology

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“…For example, recent report (Cole, Subbanagounder et al 2003) proposes a hypothetical G protein-coupled receptor involved in activation of CS-1 fibronectin production by OxPAPC. Other study indicates that epoxyisoprostane-containing products of PAPC oxidation may engage prostaglandin E2 (EP2) receptor and elevate intracellular cAMP levels (Li, Mouillesseaux et al 2006), which may promote endothelial barrier function (Moy A. B.…”

Section: Discussionmentioning

confidence: 99%

Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection

Birukova

Chatchavalvanich

Oskolkova

et al. 2007

Microvascular Research

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Increased tissue or serum levels of oxidized phospholipids have been detected in a variety of chronic and acute pathological conditions such as hyperlipidemia, atherosclerosis, heart attack, cell apoptosis, acute inflammation and injury. We have recently described signaling cascades activated by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) in the human pulmonary artery endothelial cells (EC) and reported potent barrier-protective effects of OxPAPC, which were mediated by small GTPases Rac and Cdc42. In this study we have further characterized signal transduction pathways involved in the OxPAPC-mediated endothelial barrier protection. Inhibitors of small GTPases, protein kinase A (PKA), protein kinase C (PKC), Src family kinases and general inhibitors of tyrosine kinases attenuated OxPAPC-induced barrier-protective response and EC cytoskeletal remodeling. In contrast, small GTPase Rho, Rho kinase, Erk-1,2 MAP kinase and p38 MAP kinase and PI3-kinase were not involved in the barrier-protective effects of OxPAPC. Inhibitors of PKA, PKC, tyrosine kinases and small GTPase inhibitor toxin B suppressed OxPAPC-induced Rac activation and decreased phosphorylation of focal adhesion kinase (FAK) and paxillin. Barrierprotective effects of OxPAPC were not reproduced by platelet activating factor (PAF), which at high concentrations induced barrier dysfunction, but were partially attenuated by PAF receptor antagonist A85783. These results demonstrate for the first time upstream signaling cascades involved in the OxPAPC-induced Rac activation, cytoskeletal remodeling and barrier regulation and suggest PAF receptor-independent mechanisms of OxPAPC-mediated endothelial barrier protection.

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“…In fact, it has been shown that inactivation of VLA-4 using a synthetic peptide mimetic of CS1 ( 4 ), decreased leukocyte entry and fatty streak formation in mice fed an atherogenic diet ( 19,20 ). Recent findings have also demonstrated a role for the prostaglandin receptor E2 (EP2), a G-protein coupled receptor (GPCR), in this pathway (Figure 1) 21 . Agonists of this receptor increased activation of beta 1 integrin.…”

Section: Monocyte Bindingmentioning

confidence: 99%

Endothelial cell regulation by phospholipid oxidation products

Berliner

Gharavi

2008

Free Radical Biology and Medicine

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Oxidized phospholipids accumulate in atherosclerotic lesions, on lipoproteins, in other states of chronic inflammation, on apoptotic cells, necrotic cells and cells exposed to oxidative stress. These lipids regulate the transcription of over 1000 gene, regulating many endothelial functions, by activating several different cell surface receptors and multiple signaling pathways. These lipids also have important effects not involving transcription that regulate cell junctions and leukocyte binding. Thus these lipids are potent regulators of endothelial cell function with broad effects comparable in extent but differing from those of cytokines.

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Identification of Prostaglandin E2 Receptor Subtype 2 As a Receptor Activated by OxPAPC

Cited by 103 publications

References 37 publications

Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection

Endothelial cell regulation by phospholipid oxidation products

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