Signalling role for ARF and phospholipase D in mast cell exocytosis stimulated by crosslinking of the high affinity FcεR1 receptor

Cockcroft, Shamshad; Way, Gemma; O'luanaigh, Niamh; Pardo, Raúl; Sarri, Elisabet; Fensome, Amanda

doi:10.1016/s0161-5890(02)00075-5

Cited by 36 publications

(28 citation statements)

References 24 publications

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“…We speculate that PIP 3 is required for recruitment and activation of Rac and ADP-ribosylation exchange factors, and inhibition of Rac and ADP-ribosylation factor GTPases may be responsible for inhibition of degranulation. Previous studies have shown that both ADP-ribosylation factor and Rac participate in regulating degranulation from mast cells (9,53). Because wortmannin has only a mild effect on the calcium signals and no effect on NFAT translocation but markedly inhibited IgE-evoked secretion, it appears that for optimal degranulation, signals from both arms of the pathway are required for degranulation.…”

Section: Discussionmentioning

confidence: 99%

“…This phosphorylation cascade leads to the promotion of signaling complexes organized by adaptor proteins, including linker for T cell activation, Src homology 2 domain-containing leukocyte phosphorprotein of 76 kDa, and Grb-2-associated binder 2 (GAB2) 4 (6 -8). This initiates the downstream activation of signal transducing enzymes including phospholipase C (PLC)␥, phosphoinositide 3-kinase (PI3K) (4), and phospholipase D (PLD) (9,10). These lipid-derived second messengers (phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) (recriuts and activates specific proteins), inositol 1,4,5-triphosphate (IP 3 ) (mobilizes Ca 2ϩ ), diacylglycerol (activates protein kinase C (PKC)), and phosphatidic acid (regulates phosphatidylinositol 4,5-bisphosphate production)) act in concert to evoke numerous downstream functional responses.…”

Section: Ast Cells and Basophils Are The Main Effector Cells Inmentioning

confidence: 99%

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Monomeric IgE Stimulates NFAT Translocation Into the Nucleus, a Rise in Cytosol Ca2+, Degranulation, and Membrane Ruffling in the Cultured Rat Basophilic Leukemia-2H3 Mast Cell Line

Pandey

Mihara

Fensome-Green

et al. 2004

The Journal of Immunology

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Mast cells are key regulators in allergy and inflammation, and release histamine, cytokines, and other proinflammatory mediators. In the classical view, IgE acts merely to prime mast cells, attaching to FcεRs but not evoking any cell signaling response until cross-linked by the presence of a multivalent allergen. However, several recent studies have reported that IgE alone can promote cell survival and cytokine production in the absence of cross-linking by allergen. In this study we demonstrate that acute addition of monomeric IgE elicits a wide spectrum of responses in the rat basophilic leukemia-2H3 mast cell line, including activation of phospholipases Cγ and D, a rise in cytosol Ca2+, NFAT translocation, degranulation, and membrane ruffling within minutes. Calcium transients persist for hours as long as IgE is present resulting in the maintained translocation of the transcription factor NFAT to the nucleus. Removal of IgE reverses the signaling processes. Our results indicate that, far from simply preparing the cells for a response to allergen, monomeric IgE can stimulate signaling pathways that lead to degranulation, membrane ruffling, and NFAT translocation. The mechanism of activation is likely to be via aggregation of the FcεR1 because activation by IgE can be inhibited with monovalent hapten.

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Section: Discussionmentioning

confidence: 99%

Section: Ast Cells and Basophils Are The Main Effector Cells Inmentioning

confidence: 99%

Monomeric IgE Stimulates NFAT Translocation Into the Nucleus, a Rise in Cytosol Ca2+, Degranulation, and Membrane Ruffling in the Cultured Rat Basophilic Leukemia-2H3 Mast Cell Line

Pandey

Mihara

Fensome-Green

et al. 2004

The Journal of Immunology

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“…With these functions contained within a single domain, phosphoinositide binding could influence AP-1 binding, AP-1 binding could influence phosphoinositide binding and, as described here, each can affect GAP activity. Describing these possible functional relationships will be an important step for understanding the molecular mechanisms by which Arf GAPs regulate membrane traffic and Arf, particularly considering that Arf directly activates enzymes catalyzing the production of acid phospholipids (Cockcroft et al, 2002;Honda et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

The Arf GAPs AGAP1 and AGAP2 distinguish between the adaptor protein complexes AP-1 and AP-3

Nie

Fei

Premont

et al. 2005

Journal of Cell Science

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ADP ribosylation factors (Arf) regulate membrane trafficking at multiple intracellular sites by recruiting coat proteins to membranes. The site-specific regulation of Arf is thought to be mediated by regulatory proteins including the guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Here, we test this hypothesis by comparing the site of action of the Arf GAP AGAP2 to the closely related AGAP1. AGAP1 has previously been found to associate with the adaptor protein complex AP-3 and regulate the function of AP-3 endosomes. We found that AGAP2 directly interacted with AP-1. AGAP2 colocalized with AP-1, transferrin receptor and Rab4 on endosomes. Overexpression of AGAP2 changed the intracellular distribution of AP-1 and promoted Rab4-dependent fast recycling of transferrin. Based on these results, we concluded that the closely related Arf GAPs, AGAP1 and AGAP2, distinguish between these related heterotetrameric adaptor protein complexes to specifically regulate AP-3 endosomes and AP-1 recycling endosomes.

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“…In addition, involvement of ARF1 in mast cell degranulation was reported using RBL-2H3 cells (48). Cockroft et al (48) showed that ARF1 regulates mast cell degranulation through phospholipase D activation. However, it is still unclear how ARF1 regulates the exocytotic machinery.…”

Section: Pi3k Regulates Fc«ri-mediated Granule Translocationmentioning

confidence: 99%

“…ARF1 is required for vesicular trafficking (47). In addition, involvement of ARF1 in mast cell degranulation was reported using RBL-2H3 cells (48). Cockroft et al (48) showed that ARF1 regulates mast cell degranulation through phospholipase D activation.…”

Section: Pi3k Regulates Fc«ri-mediated Granule Translocationmentioning

confidence: 99%

Gab2, via PI-3K, Regulates ARF1 in FcεRI-Mediated Granule Translocation and Mast Cell Degranulation

Nishida

Yamasaki

Hasegawa

et al. 2011

The Journal of Immunology

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Mast cells are major players in allergic responses. IgE-dependent activation through FcεR leads to degranulation and cytokine production, both of which require Gab2. To clarify how the signals diverge at Gab2, we established Gab2 knock-in mice that express Gab2 mutated at either the PI3K or SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) binding sites. Examination of these mutants showed that both binding sites were required for the degranulation and anaphylaxis response but not for cytokine production or contact hypersensitivity. Furthermore, the PI3K, but not the SHP2, binding site was important for granule translocation during degranulation. We also identified a small GTPase, ADP-ribosylation factor (ARF)1, as the downstream target of PI3K that regulates granule translocation. FcεRI stimulation induced ARF1 activation, and this response was dependent on Fyn and the PI3K binding site of Gab2. ARF1 activity was required for FcεRI-mediated granule translocation. These data indicated that Fyn/Gab2/PI3K/ARF1-mediated signaling is specifically involved in granule translocation and the anaphylaxis response.

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Signalling role for ARF and phospholipase D in mast cell exocytosis stimulated by crosslinking of the high affinity FcεR1 receptor

Cited by 36 publications

References 24 publications

Monomeric IgE Stimulates NFAT Translocation Into the Nucleus, a Rise in Cytosol Ca2+, Degranulation, and Membrane Ruffling in the Cultured Rat Basophilic Leukemia-2H3 Mast Cell Line

Monomeric IgE Stimulates NFAT Translocation Into the Nucleus, a Rise in Cytosol Ca2+, Degranulation, and Membrane Ruffling in the Cultured Rat Basophilic Leukemia-2H3 Mast Cell Line

The Arf GAPs AGAP1 and AGAP2 distinguish between the adaptor protein complexes AP-1 and AP-3

Gab2, via PI-3K, Regulates ARF1 in FcεRI-Mediated Granule Translocation and Mast Cell Degranulation

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