Review: G-protein-coupled Receptors on Eosinophils

Giembycz, Mark A.; Lynch, Oonagh T.; Souza, Patrícia Mendes de; Lindsay, Mark A.

doi:10.1006/pupt.2000.0250

Cited by 16 publications

(13 citation statements)

References 287 publications

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“…In neutrophils, mast cells, and macrophages where SHIP1 is highly expressed (11), the G i -coupled f-Met-Leu-Phe and C5a receptors raise PtdIns 3,4,5-P 3 levels via activation of the p110␥ form of PtdIns 3-kinase (2); this effect is markedly blunted by stimulation of G s -coupled receptors that raise cAMP (32,43,44). In particular, activation of the A 2a adenosine receptor has been found to inhibit the actions of inflammatory mediators in a variety of cell types (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Src Homology 2 Domain-containing Inositol 5′-Phosphatase (SHIP1) by the Cyclic AMP-dependent Protein Kinase

Zhang

Walk

Ravichandran

et al. 2009

Journal of Biological Chemistry

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Many agents that activate hematopoietic cells use phosphatidylinositol 3,4,5-trisphosphate (PtdIns 3,4,5-P 3 ) to initiate signaling cascades. The SH2 domain-containing inositol 5 phosphatase, SHIP1, regulates hematopoietic cell function by opposing the action of phosphatidylinositol 3-kinase and reducing the levels of PtdIns 3,4,5-P 3 . Activation of the cyclic AMPdependent protein kinase (PKA) also opposes many of the proinflammatory responses of hematopoietic cells. We tested to see whether the activity of SHIP1 was regulated via phosphorylation with PKA. We prepared pure recombinant SHIP1 from HEK-293 cells and found it can be rapidly phosphorylated by PKA to a stoichiometry of 0.6 mol of PO 4 /mol of SHIP1. In Overall, activation of G protein-coupled receptors that raise cyclic AMP cause SHIP1 to be phosphorylated and stimulate its inositol phosphatase activity. These results outline a novel mechanism of SHIP1 regulation. Activation of phosphatidylinositol 3-kinase (PtdIns 3-kinase)2 is central to regulation of multiple cell functions including cell shape changes, cell migration, cell activation, and proliferation (1). PtdIns 3-kinase phosphorylates phosphatidylinositol 4,5-bisphosphate in the inner leaflet of the plasma membrane to generate phosphatidylinositol 3,4,5-trisphosphate (PtdIns 3,4,5-P 3 ) (2). PtdIns 3,4,5-P 3 then activates downstream signaling pathways by interacting with pleckstrin homology domain-containing proteins, such as phosphoinositide-dependent kinase 1 and the serine-threonine kinase Akt (3). The finding of abnormal activation of the PtdIns 3-kinase pathway in cancer cells has led to interest in the development of inhibitors for PtdIns 3-kinase (4).The level of PtdIns 3,4,5-P 3 is stimulated by multiple members of the PtdIns 3-kinase family (2) and is opposed by two phosphatidylinositol phosphatases: the Src homology 2 (SH2) domain-containing inositol 5Ј phosphatase (SHIP) and the 3Ј inositol phosphatase, phosphatase and tensin homolog (PTEN) (5). PTEN removes phosphate from the 3Ј position in the inositol ring of PtdIns 3,4,5-P 3 and converts it to phosphatidylinositol 4,5-bisphosphate (6). PTEN has a C2 domain, a PDZbinding motif, and a N-terminal phosphatidylinositol 4,5-bisphosphate binding motif essential for translocation to the membrane and interaction with other regulatory proteins (7). There are serine and threonine residues in PTEN that have been found to be phosphorylated, but their role in regulating the activity of the enzyme is not clear (8). Mutations in the PTEN protein have been observed in many tumors, suggesting a role for this enzyme in cancer (9).In contrast, SHIP dephosphorylates the 5Ј position on the inositol ring and produces phosphatidylinositol 3,4-bisphosphate (10). There are three isoforms of SHIP: the 145-kDa hematopoietic cell restricted SHIP (also known as SHIP1); the 104-kDa stem cell-restricted SHIP, sSHIP; and the more widely expressed 150-kDa SHIP2 (11). SHIP1 is the major inositol phosphatase regulating PtdIns 3,4,5-P 3 in monocytes, macrophages,...

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Section: Discussionmentioning

confidence: 99%

Regulation of the Src Homology 2 Domain-containing Inositol 5′-Phosphatase (SHIP1) by the Cyclic AMP-dependent Protein Kinase

Zhang

Walk

Ravichandran

et al. 2009

Journal of Biological Chemistry

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“…In both eosinophils and neutrophils, PAF as well as other chemotactic factors operate via heterotrimeric G proteins as an intermediary, and stimulate an increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ), or activate protein kinases, and induce actin filament polymerization and chemotaxis [reviewed in 2, 33]. While human eosinophils showed nearly the same chemotactic responses characteristic of human neutrophils [34], several studies have highlighted differences between these two cell types concerning the effects of PAF apart from motility functions.…”

Section: Differences In Cellular Responses To Paf Between Human Eosinmentioning

confidence: 99%

“…Platelet-activating factor (PAF) has a variety of cellular functions [reviewed in 1, 2]including aggregation and secretion of platelets [2], aggregation and stimulation of neutrophils [3], activation of macrophages [4], an increase in vascular permeability in the skin [5], and contraction of guinea pig ileum and lung parenchymal strips [6, 7]. A specific receptor for PAF has been identified in a number of tissues and cell types including eosinophils [8, 9].…”

Section: Introductionmentioning

confidence: 99%

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Dual Signaling and Effector Pathways Mediate Human Eosinophil Activation by Platelet-Activating Factor

Katô¹,

Kita²,

Tachibana³

et al. 2004

Int Arch Allergy Immunol

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Platelet-activating factor (PAF) induces various cellular functions in eosinophils including chemotaxis, adhesion, superoxide anion (O₂^–) production, and degranulation. While PAF shares many biological effects with other chemotactic factors such as N-formyl-methionyl-leucyl-phenylalanine, complement fragments, and lipid mediators, PAF is unique in that its action is relatively resistant to pertussis toxin (PTX), and in activating eosinophils more strongly than neutrophils. In this review we consider how PAF might activate human eosinophils in preference to neutrophils, and discuss possible mechanisms of PAF-induced activation of human eosinophils via two distinct signaling and effector pathways. Recently we analyzed O₂^– production by eosinophils using a sensitive, real-time chemiluminescence method. Our results showed that in human eosinophils PAF activates two distinct signaling and effector pathways coupled to the PAF receptor: one linked to PTX-sensitive G protein(s) and another to PTX-resistant G protein(s), phosphatidylinositol 3-kinase, and cellular adhesion. This activation of two different G proteins by the eosinophil PAF receptor may explain the strong and diverse biological responses of human eosinophils to PAF.

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“…Respiratory burst and CCR3 belong to the superfamily of GPCRs that require receptor-mediated activation of certain G proteins for the transduction of intracellular signals and subsequent triggering of functional responses [17]. Blockade of the FPR with CyH or boc-MLP rendered eosinophils unable to migrate toward the CCR3 ligands eotaxin-1, -2, and -3 and RANTES.…”

Section: Chemotaxismentioning

confidence: 99%

Interplay between signaling via the formyl peptide receptor (FPR) and chemokine receptor 3 (CCR3) in human eosinophils

Svensson

Redvall

Johnsson

et al. 2009

Journal of Leukocyte Biology

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Eosinophils express the chemoattractant receptors CCR3 and FPR. CCR3 binds several agonists such as eotaxin-1, -2, and -3 and RANTES, whereas the FPR binds the formylated tripeptide fMLP and a host of other ligands. The aim of this study was to investigate if there is interplay between these two receptors regarding the elicitation of migration and respiratory burst in human blood-derived eosinophils. Inhibition of the FPR with the antagonists CyH and boc-MLP abrogated the migration of eosinophils toward all of the CCR3 agonists. Similar results were seen when the FPR was desensitized with its cognate ligand, fMLP. In contrast, the respiratory burst triggered by eotaxin-1 was not inhibited by CyH. Thus, signals evoked via the FPR caused unidirectional down-regulation of CCR3-mediated chemotaxis but not respiratory burst in human eosinophils. The underlying mechanism was neither reduced ability of the CCR3 ligand eotaxin-1 to bind to CCR3 nor down-regulation of CCR3 from the cell surface. Finally, confocal microscopy and adFRET analysis ruled out homo- or heterodimer formation between FPR and/or CCR3 as an explanation for the reduction in chemotaxis via CCR3. Pharmacologic inhibition of signal transduction molecules showed that the release of free oxygen radicals in response to eotaxin-1 compared with fMLP is relatively more dependent on the p38 MAPK pathway.

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Review: G-protein-coupled Receptors on Eosinophils

Cited by 16 publications

References 287 publications

Regulation of the Src Homology 2 Domain-containing Inositol 5′-Phosphatase (SHIP1) by the Cyclic AMP-dependent Protein Kinase

Regulation of the Src Homology 2 Domain-containing Inositol 5′-Phosphatase (SHIP1) by the Cyclic AMP-dependent Protein Kinase

Dual Signaling and Effector Pathways Mediate Human Eosinophil Activation by Platelet-Activating Factor

Interplay between signaling via the formyl peptide receptor (FPR) and chemokine receptor 3 (CCR3) in human eosinophils

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