The multiple roles of phosphoinositide 3-kinase in mast cell biology

Kim, Mi‐Sun; Rådinger, Madeleine; Gilfillan, Alasdair M.

doi:10.1016/j.it.2008.07.004

Cited by 132 publications

(128 citation statements)

References 91 publications

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“…24 These findings may be caused by, for example, expression of different sets of adhesion molecules between normal and neoplastic mast cells, or by expression of different homing receptors for (neoplastic) mast cells in the skin and extracutaneous tissues. 25,26 Consequently, the finding of KIT wild type in the skin of adult patients with mastocytosis in the skin neither correlated with mast cell density in the skin or bone marrow nor with skin lesion intensity or tryptase levels. Most importantly, it did not exclude systemic mastocytosis.…”

Section: Discussionmentioning

confidence: 97%

Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis

et al. 2014

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Adult-onset urticaria pigmentosa/mastocytosis in the skin almost always persists throughout life. The prevalence of systemic mastocytosis in such patients is not precisely known. Bone marrow biopsies from 59 patients with mastocytosis in the skin and all available skin biopsies (n ¼ 27) were subjected to a meticulous cytological, histological, immunohistochemical, and molecular analysis for the presence of WHO-defined diagnostic criteria for systemic mastocytosis: compact mast cell infiltrates (major criterion); atypical mast cell morphology, KIT D816V, abnormal expression of CD25 by mast cells, and serum tryptase levels 420 ng/ml (minor criteria). Systemic mastocytosis is diagnosed when the major diagnostic criterion plus one minor criterion or at least three minor criteria are fulfilled. Systemic mastocytosis was confirmed in 57 patients (97%) by the diagnosis of compact mast cell infiltrates plus at least one minor diagnostic criterion (n ¼ 42, 71%) or at least three minor diagnostic criteria (n ¼ 15, 25%). In two patients, only two minor diagnostic criteria were detectable, insufficient for the diagnosis of systemic mastocytosis. By the use of highly sensitive molecular methods, including the analysis of microdissected mast cells, KIT D816V was found in all 58 bone marrow biopsies investigated for it but only in 74% (20/27) of the skin biopsies. It is important to state that even in cases with insufficient diagnostic criteria for systemic mastocytosis, KIT D816V-positive mast cells were detected in the bone marrow. This study demonstrates, for the first time, that almost all patients with adult-onset mastocytosis in the skin, in fact, have systemic mastocytosis with cutaneous involvement.

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Section: Discussionmentioning

confidence: 97%

Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis

et al. 2014

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“…The PI3K family of lipid kinases plays a crucial role in many signaling pathways that regulate cell survival and growth (64). PI3K is required for mast cell mediator release as well as chemotaxis, adhesion, and homeostasis (65). It also regulates agonist-dependent, clathrin-mediated receptor endocytosis (66).…”

Section: Discussionmentioning

confidence: 99%

The Novel Receptor C5aR2 Is Required for C5a-Mediated Human Mast Cell Adhesion, Migration, and Proinflammatory Mediator Production

Pundir

MacDonald

Kulka

2015

The Journal of Immunology

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C5a generated during complement activation possesses proinflammatory and immunoregulatory properties critical for the development and modulation of allergic immune responses. In immune cells, C5a mediates its effects through binding to two G protein–coupled receptors, C5aR1 and C5aR2. Mast cells are key effectors in allergic reactions, and decades of research have suggested that the majority of C5a effects on mast cells are mediated through C5aR1, whereas the expression and function of C5aR2 have not been explored. We demonstrated that the human mast cell line Laboratory of Allergic Diseases 2 (LAD2) expresses surface C5aR2 but not C5aR1, whereas CD34+ cell–derived primary mast cells do not express surface C5aR1 or C5aR2. Stem cell factor and IL-4 upregulated C5aR2 expression on LAD2 cells. Furthermore, C5a caused internalization of LAD2 cell-surface C5aR2. We therefore used LAD2 cells as a model to study C5a/C5aR2-induced biological responses and signaling in human mast cells. We found that whereas C5a was unable to induce degranulation, it stimulated GM-CSF, TNF, CXCL10, and CCL2 production. C5a caused ERK phosphorylation, a signaling molecule important in cytokine and chemokine generation. In addition, C5a stimulated adhesion and chemotaxis of mast cells. Wortmannin, an inhibitor of PI3K, and small interfering RNA against β-arrestin-2 blocked C5a-induced adhesion. Silencing of C5aR2 using lentiviral short hairpin RNA rendered the cells unresponsive to C5a-induced adhesion, chemotaxis, and mediator release, as well as ERK phosphorylation. Overall, this study reveals a novel role for C5aR2 in C5a-mediated activation of mast cells and demonstrates that C5aR2 ligation initiates a β-arrestin-2–, PI3K-, and ERK-dependent signaling pathway in these cells.

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“…Class I A PI3K, which consists of regulatory and catalytic subunits, is involved in multiple signal-transduction cascades that regulate cell proliferation, survival, and differentiation (39). Various receptor-signaling pathways, including those mediated by KitL and FcεRI, can activate the class I A PI3K in mast cells (40)(41)(42)(43). Many investigators, including us, showed that the treatment of mast cells with the PI3K inhibitors wortmannin or LY294002 suppresses FcεRI-mediated mast cell degranulation, suggesting that PI3K is required for this process (44)(45)(46).…”

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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The multiple roles of phosphoinositide 3-kinase in mast cell biology

Cited by 132 publications

References 91 publications

Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis

Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis

The Novel Receptor C5aR2 Is Required for C5a-Mediated Human Mast Cell Adhesion, Migration, and Proinflammatory Mediator Production

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

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