Loss of TRPC1-mediated Ca2+ influx contributes to impaired degranulation in Fyn-deficient mouse bone marrow-derived mast cells

Suzuki, Ryo; Liu, Xibao; Olivera, Ana; Aguiniga, Lizath; Yamashita, Yuichi; Blank, Ulrich; Ambudkar, Indu S.; Rivera, Juan

doi:10.1189/jlb.0510253

Cited by 59 publications

(68 citation statements)

References 70 publications

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“…We found that granule exocytosis occurs more frequently along extended cell protrusions when Ca 2+ waves initiate from these structures, particularly at limiting antigen concentration. Under these conditions, Ca 2+ influx through TRPC1 contributed significantly to granule exocytosis in these cells, consistent with our previous results indicating its participation in Ca 2+ wave initiation from protrusions (Cohen et al, 2009) and with recent evidence for its role in stimulated degranulation in mouse bonemarrow-derived mast cells (Suzuki et al, 2010).…”

Section: Discussionsupporting

confidence: 79%

Spatiotemporal Resolution of Mast Cell Granule Exocytosis

Cohen

Corwith

Holowka

et al. 2012

Journal of Cell Science

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SummaryMast cell activation initiated by antigen-mediated crosslinking of IgE receptors results in stimulated exocytosis of secretory lysosomes in the process known as degranulation. Much has been learned about the molecular mechanisms important for this process, including the crucial role of Ca 2+ mobilization, but spatio-temporal relationships between stimulated Ca 2+ mobilization and granule exocytosis are incompletely understood. Here we use a novel imaging-based method that uses fluorescein isothiocyanate (FITC)-dextran as a reporter for granule exocytosis in RBL mast cells and takes advantage of the pH sensitivity of FITC. We demonstrate the selectivity of FITCdextran, accumulated by fluid-phase uptake, as a marker for secretory lysosomes, and we characterize its capacity to delineate different exocytotic events, including full fusion, kiss-and-run transient fusion and compound exocytosis. Using this method, we find strong dependence of degranulation kinetics on the duration of cell to substrate attachment. We combine imaging of degranulation and Ca 2+ dynamics to demonstrate a spatial relationship between the sites of Ca 2+ wave initiation in extended cell protrusions and exocytosis under conditions of limited antigen stimulation. In addition, we find that the spatially proximal Ca 2+ signaling and secretory events correlate with participation of TRPC1 channels in Ca 2+ mobilization.

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Section: Discussionsupporting

confidence: 79%

Spatiotemporal Resolution of Mast Cell Granule Exocytosis

Cohen

Corwith

Holowka

et al. 2012

Journal of Cell Science

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“…2ϩ influx, F-actin depolymerization, and subsequent degranulation in activated mast cells (27). Considering that STAT5 tyrosine phosphorylation is an early response to Fc⑀RI engagement, it was important to determine whether TRPC1 has any input in this activation.…”

Section: Lack Of Transient Receptor Potential Channel 1 (Trpc1) Doesmentioning

confidence: 99%

Novel Mechanism for FcϵRI-mediated Signal Transducer and Activator of Transcription 5 (STAT5) Tyrosine Phosphorylation and the Selective Influence of STAT5B over Mast Cell Cytokine Production

Pullen

Barnstein

Falanga

et al. 2012

Journal of Biological Chemistry

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Background: STAT5 is a transcription factor that is vital for mast cell function. Results: Loss of Fyn kinase prevents, whereas loss of Lyn, Gab2, or SHP-1 enhances, Fc⑀RI-mediated STAT5 tyrosine phosphorylation. Conclusion: IgE-mediated STAT5 activation in mast cells requires Fyn kinase.Significance: Elucidating the mechanisms of mast cell activity is essential to understanding and treating allergic pathologies.

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“…PI3K is crucial for the propagation of the Fyn cascade, since it induces the activation of Akt, the production of PIP 3 (by phosphorylation of PIP 2 ), and thereby provides tethering to the Tec kinase Btk. Fyn appears to be important in the calcium influx signaling deriving from the activation of nonselective Ca 2+ channels, such as TRPC-1 [20], which contributes to store-operated calcium entry. Fyn signaling may be finely-modulated by the action of membrane phosphatases, such as the SHPs, which have been the object of investigation in a series of recent papers [21][22][23].…”

Section: Fynmentioning

confidence: 99%

Mast cell activation: A complex interplay of positive and negative signaling pathways

Sibilano¹,

2014

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Mast cells regulate the immunological responses causing allergy and autoimmunity, and contribute to the tumor microenvironment through generation and secretion of a broad array of preformed, granule-stored and de novo synthesized bioactive compounds. The release and production of mast cell mediators is the result of a coordinated signaling machinery, followed by the FcεRI and FcγR antigen ligation. In this review, we present the latest understanding of FcεRI and FcγR signaling, required for the canonical mast cell activation during allergic responses and anaphylaxis. We then describe the cooperation between the signaling of FcR and other recently characterized membrane-bound receptors (i.e., IL-33R and thymic stromal lymphopoietin receptor) and their role in the chronic settings, where mast cell activation is crucial for the development and the sustainment of chronic diseases, such as asthma or airway inflammation. Finally, we report how the FcR activation could be used as a therapeutic approach to treat allergic and atopic diseases by mast cell inactivation. Understanding the magnitude and the complexity of mast cell signaling is necessary to identify the mechanisms underlying the potential effector and regulatory roles of mast cells in the biology and pathology of those disease settings in which mast cells are activated.Keywords: FcεRI r FcγR r IL-33 r mast cells r TSLP IntroductionMast cells originate in the BM from a lineage-specific multipotent hematopoietic progenitor, circulate as CD34 + precursors until they migrate to tissues and mature into effector cells in the proximity of organs and blood vessels. Mast cells respond to antigenic stimulation through the cross-linking of immunoglobulin E (IgE) bound to high-affinity receptors for IgE (FcεRI) and the activation of the FcγR after IgG binding (reviewed in [1,2]). Upon activation, mast cells release either preformed, granule-stored mediators, such as histamine and proteases, or newly generated mediators, such as eicosanoids, cytokines, and chemokines [3]. Although the basic molecular mechanisms of Ig:Fc activation have been extensively studied in the past 15 years [4][5][6], new molecules regulating the Correspondence: Dr. Barbara Frossi e-mail: barbara.frossi@uniud.it FcR-signaling cascades have recently been characterized, suggesting not only a still vivid interest in the field of mast cell activation and signaling, but also in identifying putative new therapeutic targets for intervention in mast cell dependent disorders. This review will focus on three aspects of mast cell activation/function. First, we give an essential but complete overview of the FcR-mediated activation in mast cells and report on recent advances in IgE-and IgG-mediated signaling. For clarity, we will dissect and analyze the signals derived from each pathway, with particular attention to the newly identified positive or negative molecular players describing -when possible -their implication toward degranulation and cytokine production. Second, we highlight the growing interest aroun...

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Loss of TRPC1-mediated Ca2+ influx contributes to impaired degranulation in Fyn-deficient mouse bone marrow-derived mast cells

Cited by 59 publications

References 70 publications

Spatiotemporal Resolution of Mast Cell Granule Exocytosis

Spatiotemporal Resolution of Mast Cell Granule Exocytosis

Novel Mechanism for FcϵRI-mediated Signal Transducer and Activator of Transcription 5 (STAT5) Tyrosine Phosphorylation and the Selective Influence of STAT5B over Mast Cell Cytokine Production

Mast cell activation: A complex interplay of positive and negative signaling pathways

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