Cooperation between the FcϵR1 and Formyl Peptide Receptor Signaling Pathways in RBLFPRCells: The Contribution of Receptor-Specific Ca2+Mobilization Responses

Lee, Rebecca; Lujan, Don; Hall, Anne L.; Sklar, Larry A.; Wilson, Bridget S.; Oliver, Janet M.

doi:10.1006/bbrc.1997.6874

Cited by 12 publications

(16 citation statements)

References 34 publications

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“…Previous studies examining the degranulation response of stable RBL-FPR demonstrated ϳ22.5% (16) release of ␤-hexosaminidase and little to no release of preloaded [ 3 H]serotonin, (15). These RBL-2H3 cell lines used in these studies stably expressed between 90,000 and 200,000 receptors.…”

Section: Discussionmentioning

confidence: 77%

“…The RBL-2H3 mast cell line has previously been used to characterize GPCR-mediated signaling events that culminate in degranulation (15,16,21). The regulation of this degranulation event in response to stimulation plays an important role in controlling the cytotoxic potential of leukocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation of the FPR in RBL-2H3 cells transfected with the FPR has provided ambiguous results with respect to degranulation (15,16 conflicting data regarding the roles of receptor phosphorylation and accessory proteins in mediating degranulation initiated by binding of ligands to their cognate receptors (13,17). To examine the role of receptor phosphorylation and arrestin in the regulation of signaling events that mediate the degranulation of RBL-2H3 cells upon stimulation of the FPR, we used a mutant of the FPR that lacks phosphorylation sites in the C terminus.…”

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confidence: 99%

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Regulation of N-Formyl Peptide-Mediated Degranulation by Receptor Phosphorylation

Vines

Xue

Maestas

et al. 2002

The Journal of Immunology

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One of the major functions of the N-formyl peptide receptor (FPR) is to mediate leukocyte degranulation. Phosphorylation of the C-terminal domain of the FPR is required for receptor internalization and desensitization. Although arrestins mediate phosphorylation-dependent desensitization, internalization, and initiation of novel signaling cascades for a number of G protein-coupled receptors, their roles in FPR regulation and signaling remain unclear. CXCR1-mediated degranulation of RBL-2H3 cells is promoted by arrestin binding. To determine whether receptor phosphorylation or arrestin binding is required to promote FPR-mediated degranulation, we used RBL-2H3 cells stably transfected with either the wild-type FPR or a mutant form, ΔST, which is incapable of undergoing ligand-stimulated phosphorylation. We observed that stimulation of wild-type FPR resulted in very low levels of degranulation compared with that mediated by cross-linking of the FcεRI receptor. Stimulation of the ΔST mutant, however, resulted in levels of degranulation comparable to those of the FcεRI receptor, demonstrating that neither receptor phosphorylation nor arrestin binding was necessary to initiate FPR-mediated degranulation. Degranulation initiated by the ΔST mutant was proportional to the level of active cell surface receptor, suggesting that either receptor internalization or desensitization may be responsible for terminating degranulation of the wild-type FPR. To distinguish between these possibilities, we used a partially phosphorylation-deficient mutant of the FPR that can undergo internalization, but not desensitization. Degranulation by this mutant FPR was indistinguishable from that of the ΔST mutant, indicating that FPR phosphorylation or binding of arrestin but not internalization terminates the degranulation response.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of N-Formyl Peptide-Mediated Degranulation by Receptor Phosphorylation

Vines

Xue

Maestas

et al. 2002

The Journal of Immunology

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“…CXCR4 was strongly up-regulated in Lyn Ϫ/Ϫ BMMCs. Ligation of G protein-coupled receptors can prime mast cells for increased Fc⑀RI-mediated degranulation (27).…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Genes Linked to FcεRI Signaling and to Cytokine and Chemokine Production in Lyn-Deficient Mast Cells

Hernandez-Hansen

Bard

Tarleton

et al. 2005

The Journal of Immunology

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Cross-linking the high-affinity IgE receptor, FcεRI, on mast cells activates signaling pathways leading to the release of preformed inflammatory mediators and the production of cytokines and chemokines associated with allergic disorders. Bone marrow-derived mast cells (BMMCs) from Lyn-deficient (Lyn−/−) mice are hyperresponsive to FcεRI cross-linking with multivalent Ag. Previous studies linked the hyperresponsive phenotype in part to increased Fyn kinase activity and reduced SHIP phosphatase activity in the Lyn−/− BMMCs in comparison with wild-type (WT) cells. In this study, we compared gene expression profiles between resting and Ag-activated WT and Lyn−/− BMMCs to identify other factors that may contribute to the hyperresponsiveness of the Lyn−/− cells. Among genes implicated in the positive regulation of FcεRI signaling, mRNA for the tyrosine kinase, Fyn, and for several proteins contributing to calcium regulation are more up-regulated following Ag stimulation in Lyn−/− BMMCs than in WT BMMCs. Conversely, mRNA for the low-affinity IgG receptor (FcγRIIB), implicated in negative regulation of FcεRI-mediated signaling, is more down-regulated in Ag-stimulated Lyn−/− BMMCs than in WT BMMCs. Genes coding for proinflammatory cytokines and chemokines (IL-4, IL-6, IL-13, CSF, CCL1, CCL3, CCL5, CCL7, CCL9, and MIP1β)are all more highly expressed in Ag-stimulated Lyn−/− mast cells than in WT cells. These microarray data identify Lyn as a negative regulator in Ag-stimulated BMMCs of the expression of genes linked to FcεRI signaling and also to the response pathways that lead to allergy and asthma.

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“…This initial kinase activation results in stimulation of two isoforms of phospholipase C-␥, PLC␥1 and PLC␥2, and leads to elevated levels of inositol 1,4,5-trisphosphate (InsP 3 ) that are sustained over prolonged periods (Ͼ10 -15 min) of cross-linking (reviewed in Wilson et al, 1997). Previous evidence has shown that phosphatidylinositol 3-kinase supports the activation and phosphorylation of PLC␥1 and is required for maximal InsP 3 synthesis (Barker et al, 1995 (Fasolato, et al, 1993), although there is evidence that a second Ca 2ϩ influx pathway also participates in Ca 2ϩ entry into antigenstimulated RBL-2H3 cells (Lee and Oliver, 1995).…”

Section: Introductionmentioning

confidence: 99%

Calcium-dependent Clustering of Inositol 1,4,5-Trisphosphate Receptors

Wilson

Pfeiffer

Smith

et al. 1998

MBoC

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Rat basophilic leukemia (RBL-2H3) cells predominantly express the type II receptor for inositol 1,4,5-trisphosphate (InsP 3 ), which operates as an InsP 3 -gated calcium channel. In these cells, cross-linking the high-affinity immunoglobulin E receptor (Fc⑀R1) leads to activation of phospholipase C ␥ isoforms via tyrosine kinase-and phosphatidylinositol 3-kinase-dependent pathways, release of InsP 3 -sensitive intracellular Ca 2ϩ stores, and a sustained phase of Ca 2ϩ influx. These events are accompanied by a redistribution of type II InsP 3 receptors within the endoplasmic reticulum and nuclear envelope, from a diffuse pattern with a few small aggregates in resting cells to large isolated clusters after antigen stimulation. Redistribution of type II InsP 3 receptors is also seen after treatment of RBL-2H3 cells with ionomycin or thapsigargin. InsP 3 receptor clustering occurs within 5-10 min of stimulus and persists for up to 1 h in the presence of antigen. Receptor clustering is independent of endoplasmic reticulum vesiculation, which occurs only at ionomycin concentrations Ͼ1 M, and maximal clustering responses are dependent on the presence of extracellular calcium. InsP 3 receptor aggregation may be a characteristic cellular response to Ca 2ϩ -mobilizing ligands, because similar results are seen after activation of phospholipase C-linked G-protein-coupled receptors; cholecystokinin causes type II receptor redistribution in rat pancreatoma AR4 -2J cells, and carbachol causes type III receptor redistribution in muscarinic receptor-expressing hamster lung fibroblast E36 M3R cells. Stimulation of these three cell types leads to a reduction in InsP 3 receptor levels only in AR4 -2J cells, indicating that receptor clustering does not correlate with receptor down-regulation. The calcium-dependent aggregation of InsP 3 receptors may contribute to the previously observed changes in affinity for InsP 3 in the presence of elevated Ca 2ϩ and/or may establish discrete regions within refilled stores with varying capacity to release Ca 2ϩ when a subsequent stimulus results in production of InsP 3 . INTRODUCTIONCross-linking the immunoglobulin E (IgE)-primed Fc⑀ receptor 1 (Fc⑀R1) of rat basophilic leukemia (RBL-2H3) cells leads to Lyn-mediated phosphorylation of immunoreceptor tyrosine activation motifs within the cytoplasmic tails of Fc⑀R1 ␤ and ␥ subunits, followed by recruitment and activation of the tyrosine kinase Syk (reviewed in Benhamou, 1997). This initial kinase activation results in stimulation of two isoforms of phospholipase C-␥, PLC␥1 and PLC␥2, and leads to elevated levels of inositol 1,4,5-trisphosphate (InsP 3 ) that are sustained over prolonged periods (Ͼ10 -15 min) of cross-linking (reviewed in Wilson et al., 1997). Previous evidence has shown that phosphatidylinositol 3-kinase supports the activation and phosphorylation of PLC␥1 and is required for maximal InsP 3 synthesis (Barker et al., 1995 (Fasolato, et al., 1993), although there is evidence that a second Ca 2ϩ influx pathway also participates in Ca...

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Cooperation between the FcϵR1 and Formyl Peptide Receptor Signaling Pathways in RBLFPRCells: The Contribution of Receptor-Specific Ca2+Mobilization Responses

Cited by 12 publications

References 34 publications

Regulation of N-Formyl Peptide-Mediated Degranulation by Receptor Phosphorylation

Regulation of N-Formyl Peptide-Mediated Degranulation by Receptor Phosphorylation

Increased Expression of Genes Linked to FcεRI Signaling and to Cytokine and Chemokine Production in Lyn-Deficient Mast Cells

Calcium-dependent Clustering of Inositol 1,4,5-Trisphosphate Receptors

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