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Class IA PI3Kinase regulatory subunit p85α regulates mast cell growth and survival related genes

ABSTRACT: Stem cell factor (SCF) mediated KIT receptor activation plays a pivotal role in mast cell growth, maturation and survival. However, the signaling events downstream from KIT are poorly understood. Mast cells express multiple regulatory subunits of class 1A PI3Kinase (PI3K) including p85α, p85β, p50α, and p55α. While it is known that PI3K plays an essential role in mast cells; the precise mechanism by which these regulatory subunits impact specific mast cell functions including growth, survival and cycling are not known. We show that loss of p85α impairs the growth, survival and cycling of mast cell progenitors (MCp). To delineate the molecular mechanism (s) by which p85α regulates mast cell growth, survival and cycling, we performed microarray analyses to compare the gene expression profile of MCps derived from WT and p85α-deficient mice in response to SCF stimulation. We identified 151 unique genes exhibiting altered expression in p85α-deficient cells in response to SCF stimulation compared to WT cells. Functional categorization based on DAVID bioinformatics tool and Ingenuity Pathway Analysis (IPA) software relates the altered genes due to lack of p85α to transcription, cell cycle, cell survival, cell adhesion, cell differentiation, and signal transduction. Our results suggest that p85α is involved in mast cell development through regulation of expression of growth, survival and cell cycle related genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE32410 | GEO | 2011/09/28

SECONDARY ACCESSION(S): PRJNA146389

REPOSITORIES: GEO

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Class IA PI3Kinase regulatory subunit p85α regulates mast cell growth and survival related genes

Project description:Stem cell factor (SCF) mediated KIT receptor activation plays a pivotal role in mast cell growth, maturation and survival. However, the signaling events downstream from KIT are poorly understood. Mast cells express multiple regulatory subunits of class 1A PI3Kinase (PI3K) including p85α, p85β, p50α, and p55α. While it is known that PI3K plays an essential role in mast cells; the precise mechanism by which these regulatory subunits impact specific mast cell functions including growth, survival and cycling are not known. We show that loss of p85α impairs the growth, survival and cycling of mast cell progenitors (MCp). To delineate the molecular mechanism (s) by which p85α regulates mast cell growth, survival and cycling, we performed microarray analyses to compare the gene expression profile of MCps derived from WT and p85α-deficient mice in response to SCF stimulation. We identified 151 unique genes exhibiting altered expression in p85α-deficient cells in response to SCF stimulation compared to WT cells. Functional categorization based on DAVID bioinformatics tool and Ingenuity Pathway Analysis (IPA) software relates the altered genes due to lack of p85α to transcription, cell cycle, cell survival, cell adhesion, cell differentiation, and signal transduction. Our results suggest that p85α is involved in mast cell development through regulation of expression of growth, survival and cell cycle related genes. Two-condition experiment, wildtype vs. p85α-deficient mast cell progenitors stimulated with SCF. Biological replicates: 3 wildtype replicates, 3 p85α-deficient replicates.

2011-09-27 | E-GEOD-32410 | biostudies-arrayexpress

Mus musculus

Project description:Class IA PI3Kinase regulatory subunit p85α regulates mast cell growth and survival related genes

| PRJNA146389 | ENA

Stem cell factor programs the mast cell activation phenotype

Project description:Mast cells, activated by antigen via the high affinity receptor for IgE (FcεRI), release an array of pro-inflammatory mediators that contribute to allergic disorders such as asthma and anaphylaxis. The KIT ligand, stem cell factor (SCF), is critical for mast cell expansion, differentiation and survival, and, under acute conditions, enhances mast cell activation. However, extended SCF exposure in vivo conversely protects against fatal antigen-mediated anaphylaxis. In investigating this dichotomy, we identified a novel mode of regulation of the mast cell activation phenotype through SCF-mediated programming. We found that mouse bone marrow-derived mast cells chronically exposed to SCF displayed a marked attenuation of FcεRI-mediated degranulation and cytokine production. The hypo-responsive phenotype was not a consequence of altered signals regulating calcium flux or protein kinase C, but of ineffective cytoskeletal reorganization, with evidence implicating a down-regulation of expression of the Src kinase Hck. Collectively, these findings demonstrate a major role for SCF in the homeostatic control of mast cell activation with potential relevance to mast cell-driven disease and the development of novel approaches for the treatment of allergic disorders. Mouse bone marrow-derived mast cells were treated with IL3, IL3+IL33, or IL3+SCF. Six replicates each.

2012-05-01 | E-GEOD-35332 | biostudies-arrayexpress

Stem cell factor programs the mast cell activation phenotype

2012-05-02 | GSE35332 | GEO

Adult Connective Tissue-Resident Mast Cells Originate from Late Erythro-Myeloid Progenitors [development]

Project description:Purpose: The purpose is to systemically identify RNA expression changes along mast cell development during embryogenesis. Methods: We profiled RNA-seq in early EMPs and their progeny. Results: Fetal MCPs acquire the mast cell-specific gene signature from E11.5 and complete their maturation in peripheral tissues.

2018-10-15 | GSE119017 | GEO

Mast cell microRNAs regulated by KIT signaling

Project description:Objective is to identify microRNAs regulated by KIT signaling in mast cells. miRNA profiles of murine bone marrow derived mast cells with and without SCF treatment were compared. In addition, miRNA profiles of the P815 mutant KIT cell line with and without the KIT inhibitor, imatinib, were compared. We identified miRNAs that were differentially regulated by KIT signals. Two systems were used to identify microRNAs regulated by KIT. RNA was collected from primary murine bone marrow derived mast cells (BMMC) treated and not treated with KIT ligand (SCF). In addition, RNA was harvested from the P815 (activating KIT mutation positive) cell line treated and not treated with the KIT inhibitor, imatinib. Samples were harvested after 24 hours of treatment

2011-01-25 | E-GEOD-26783 | biostudies-arrayexpress

Lung-specific MCEMP1 acts as an adaptor for KIT to promote SCF-mediated mast cell proliferation [PCMC RNA-seq]

Project description:We analyzed transcriptomic changes in Mcemp1-/- Peritoneal cell-derived mast cells (PCMC) versus Mcemp1 wild-type PCMC cultured with SCF and IL-3 for 9-days.

2023-03-13 | GSE197041 | GEO

Role of IL-2 inducible T cell kinase (ITK) and Bruton's tyrosine kinase (BTK) in mast cell response to lipopolysaccharide (LPS)

Project description:Mast cells are indispensable for LPS-induced septic hypothermia, in which TNF-Î± plays an essential role to initiate sepsis. Tec family non-receptor tyrosine kinases ITK and BTK regulate mast cell-derived TNF-Î± in response to allergic antigen, but their role in LPS-induced TNF-Î± production by mast cells and related pathology is unclear. We sought to investigate the role(s) of ITK and BTK in mast cell response in septic condition. We found that the absence of ITK and BTK leads to enhanced TNF-Î± production by bone marrow-derived mast cells (BMMC). Itk-/-Btk-/- mast cells exhibit hyperactive preformed and LPS-induced TNF-Î± production, along with enhanced expression of other related genes such as NF-ÎºB targeted genes, compared to WT cells. Bone marrow cells from 8-week old WT, Itk-/-, Btk-/- and Itk-/-Btk-/- (double knockout: DKO) C57Bl/6 mice were cultured in murine Interleukin-3/Stem cell factor (IL-3/SCF) supplemented medium for 5 weeks to derive mast cells. WT, Itk-/-, Btk-/- and DKO bone marrow-derived mast cells (BMMC) were factor starved in medium without IL-3/SCF for 12 hours, followed by treatment with PBS (control) or 100 ng/ml LPS for 1 hour. Triplicates of each group were subjected to mouse whole genome genechip microarray analysis. Replicates were randomized on different chips to avoid systematic error.

2015-11-23 | E-GEOD-64287 | biostudies-arrayexpress

SCF -licensed induction of a mucosal mast cell-like transcriptional program by TGF-b

Project description:This study evaluates the effects of 72h stimulus with stem cell factor (SCF) (100 ng/mL) and TGF-b (1 ng/mL or 10 ng/mL), both alone and in combination, on the transcriptome of bone marrow-derived cultured mast cells (BMMCs) grown in IL-3 for 6-8 weeks. Through this approach, we find that SCF dramatically enhances TGF-b mediated upregulation of signature genes associated with mucosal mast cells, including transcripts encoding the proteases mMCP-1 (Mcpt1) and mMCP-2 (Mcpt2). Replicates indicate biologic duplicates. Samples were sequenced on an Illumina NextSeq 500.

2020-08-03 | GSE155571 | GEO

Global phosphoproteomics in SCF stimulated human skin mast cells

Project description:Global phosphoproteomics can reveal signaling cascades in unprecedented detail. The SCF/KIT axis represents a vital hematopoietic receptor tyrosine kinase (RTK) system with gain-of-function mutations prompting the development of mastocytosis and leukemia. Here, we employed a label-free phosphoproteomics profiling strategy to provide the first comprehensive portrayal of SCF-triggered phosphosignaling. Employing untransformed skin-derived mast cells expressing vast amounts of KIT, we uncover around 10,500 class-I-phosphosites following ligand-induced KIT dimerization. Apart from STAT5, the MEK/ERK cascade (including upstream and downstream events) stood out as highly stimulatable by SCF compared to less impacted PI3K/Akt>p38>JNK, a pattern validated by time-resolved immunoblotting. Direct comparison between MEK/ERKÕs and PI3KÕs support of basic programs (anti-apoptosis, cell cycle progression) revealed equipotency with substantial redundancy between the modules. In functional outputs, ERK showed dominance over PI3K regarding cytokine stimulation (TNF-a, IL-8, LIF, OSM) and was the only contributor in the induction of immediate early genes (Fos, JunB, Egr1). Our proteome-wide screen also found Å1,000 phosphosites currently undescribed in databases, pertaining to multiple protein classes. Among candidates, capicua (and components of its network) experienced massive phosphorylation by SCF. Perturbation with capicua by RNA interference unveiled its function as a potent KIT repressor, whose deregulation may contribute to the development of mastocytosis. We demonstrate the utility of an unbiased approach to uncover single protein entities and entire networks activated by RTKs, that can be surveyed experimentally. This rich resource enhances our understanding of RTK-elicited signaling networks and can serve as a benchmark to identify pathological processes, e.g. under circumstances of KIT deregulation.

2022-03-31 | PXD028245 | Pride

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