The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor

Ma, Peilin; Mali, Raghuveer Singh; Munugalavadla, Veerendra; Krishnan, Subha; Ramdas, Baskar; Sims, Emily; Martin, Holly; Ghosh, Joydeep; Li, Shuo; Chan, Rebecca J.; Krystal, Gerald; Craig, Andrew W.B.; Takemoto, Clifford M.; Kapur, Reuben

doi:10.1182/blood-2011-04-351809

Cited by 27 publications

(30 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Specifically, activation of the PI3-K/AKT pathway was shown to contribute to KIT-dependent proliferation, survival, maturation, adhesion, or activation. 52 Interestingly, the introduction of KIT D816V in ROSA cells induced the constitutive activation of AKT, which is in line with previously reported data. 53 In addition, KIT D816V recruits alternative signaling pathways not evoked by KIT WT, particularly STAT5.…”

Section: Discussionsupporting

confidence: 90%

A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection

Saleh

Wedeh

Herrmann

et al. 2014

Blood

103

View full text Add to dashboard Cite

Key Points• ROSA KIT WT is a new human SCF-dependent FceRI-positive mast cell line that converts to SCF-independence by KIT D816V-transfection.• The FceRI-positive ROSA KIT D816V clone is a major tool for studying cellular aspects of mastocytosis and responses to targeted drugs.In systemic mastocytosis (SM), clinical problems arise from factor-independent proliferation of mast cells (MCs) and the increased release of mediators by MCs, but no human cell line model for studying MC activation in the context of SM is available. We have created a stable stem cell factor (SCF) -dependent human MC line, ROSA -derived tumors did not show mediator-related symptoms, and KIT D816V-positive MCs obtained from patients with SM did not show increased IgE-dependent histamine release or CD63 upregulation. Our data show that KIT D816V is a disease-propagating oncoprotein, but it does not activate MCs to release proinflammatory mediators, which may explain why mediator-related symptoms in SM occur preferentially in the context of a coexisting allergy. ROSA KIT D816V may provide a valuable tool for studying the pathogenesis of mastocytosis and should facilitate the development of novel drugs for treating SM patients. (Blood. 2014;124(1):111-120)

show abstract

Section: Discussionsupporting

confidence: 90%

A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection

Saleh

Wedeh

Herrmann

et al. 2014

Blood

103

View full text Add to dashboard Cite

show abstract

“…However, although we could express these SHIP constructs in Phoenix Ampho 293T producer cell lines, we were unsuccessful in achieving detectable expression, using either lipofectamine or retroviral infection, in mature SHIP −/− CTMCs, BMMCs, or BM progenitors. While engaged in these studies, Ma et al (47) reported that IL-3–stimulated BMMCs that were deficient in PI3K p85α were far less capable of activating Akt than WT BMMCs. We therefore investigated whether Akt was also less activated in response to LPS in these p85α −/− BMMCs.…”

Section: Resultsmentioning

confidence: 99%

The Role of SHIP in the Development and Activation of Mouse Mucosal and Connective Tissue Mast Cells

Rüschmann

Antignano

Lam

et al. 2012

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Although SHIP is a well-established suppressor of IgE plus Ag-induced degranulation and cytokine production in bone marrow-derived mast cells (BMMCs), little is known about its role in connective tissue (CTMCs) or mucosal (MMCs) mast cells. In this study, we compared SHIP’s role in the development as well as the IgE plus Ag and TLR-induced activation of CTMCs, MMCs, and BMMCs and found that SHIP delays the maturation of all three mast cell subsets and, surprisingly, that it is a positive regulator of IgE-induced BMMC survival. We also found that SHIP represses IgE plus Ag-induced degranulation of all three mast cell subsets and that TLR agonists do not trigger their degranulation, whether SHIP is present or not, nor do they enhance IgE plus Ag-induced degranulation. In terms of cytokine production, we found that in MMCs and BMMCs, which are poor producers of TLR-induced cytokines, SHIP is a potent negative regulator of IgE plus Ag-induced IL-6 and TNF-α production. Surprisingly, however, in splenic or peritoneal derived CTMCs, which are poor producers of IgE plus Ag-induced cytokines, SHIP is a potent positive regulator of TLR-induced cytokine production. Lastly, cell signaling and cytokine production studies with and without LY294002, wortmannin, and PI3Kα inhibitor-2, as well as with PI3K p85α−/− BMMCs and CTMCs, are consistent with SHIP positively regulating TLR-induced cytokine production via an adaptor-mediated pathway while negatively regulating IgE plus Ag-induced cytokine production by repressing the PI3K pathway.

show abstract

“…In our experiments, priming of BMMCs with Notch ligands for 6 d is thought to promote differentiation and maturation of the cells through Notch2 signaling. Recent studies have shown that a decrease in SHIP-1 expression relates to maturation of mast cells (38,39). Additionally, the cellular content of histamine was decreased in BMMCs by priming with Notch ligands (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Notch Signaling Enhances FcεRI-Mediated Cytokine Production by Mast Cells through Direct and Indirect Mechanisms

Nakano

Nishiyama

Yagita

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Th2-type cytokines and TNF-α secreted by activated mast cells upon cross-linking of FcεRI contribute to the development and maintenance of Th2 immunity to parasites and allergens. We have previously shown that cytokine secretion by mouse mast cells is enhanced by signaling through Notch receptors. In this study, we investigated the molecular mechanisms by which Notch signaling enhances mast cell cytokine production induced by FcεRI cross-linking. FcεRI-mediated production of cytokines, particularly IL-4, was significantly enhanced in mouse bone marrow–derived mast cells by priming with Notch ligands. Western blot analysis showed that Notch signaling augmented and prolonged FcεRI-mediated phosphorylation of MAPKs, mainly JNK and p38 MAPK, through suppression of the expression of SHIP-1, a master negative regulator of FcεRI signaling, resulting in the enhanced production of multiple cytokines. The enhancing effect of Notch ligand priming on multiple cytokine production was abolished by knockdown of Notch2, but not Notch1, and FcεRI-mediated production of multiple cytokines was enhanced by retroviral transduction with the intracellular domain of Notch2. However, only IL-4 production was enhanced by both Notch1 and Notch2. The enhancing effect of Notch signaling on IL-4 production was lost in bone marrow–derived mast cells from mice lacking conserved noncoding sequence 2, which is located at the distal 3′ element of the Il4 gene locus and contains Notch effector RBP-J binding sites. These results indicate that Notch2 signaling indirectly enhances the FcεRI-mediated production of multiple cytokines, and both Notch1 and Notch2 signaling directly enhances IL-4 production through the noncoding sequence 2 enhancer of the Il4 gene.

show abstract

The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor

Cited by 27 publications

References 31 publications

A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection

A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection

The Role of SHIP in the Development and Activation of Mouse Mucosal and Connective Tissue Mast Cells

Notch Signaling Enhances FcεRI-Mediated Cytokine Production by Mast Cells through Direct and Indirect Mechanisms

Contact Info

Product

Resources

About