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, Nick; Barnstein, Brian; Falanga, Yves T.; Wang, Zhengqi; Suzuki, Ryo; Tamang, Tenchee D. Lama; Khurana, Michele; Harry, Emily A.; Dráber, Petr; Bunting, Kevin D.; Mizuno, Kazuya; Wilson, Bridget S.; Ryan, John

doi:10.1074/jbc.m111.311142

Cited by 34 publications

(46 citation statements)

References 42 publications

(63 reference statements)

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“…We recently found that Stat5, activated by Fyn kinase, is critical for IgE-mediated signaling (22, 23). In addition to Fyn and Stat5, FcεRI activates Syk kinase, which, along with Fyn, induces Akt activation (33).…”

Section: Resultsmentioning

confidence: 99%

Genotype-Dependent Effects of TGF-β1 on Mast Cell Function: Targeting the Stat5 Pathway

Fernando

Faber

Pullen

et al. 2013

The Journal of Immunology

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We previously demonstrated that Transforming Growth Factor (TGF) β1 suppresses IgE-mediated signaling in human and mouse mast cells in vitro, an effect that correlated with decreased expression of the high affinity IgE receptor, FcεRI. The in vivo effects of TGFβ1 and the means by which it suppresses mast cells have been less clear. The current study shows that TGFβ1 suppresses FcεRI and c-Kit expression in vivo. By examining changes in cytokine production concurrent with FcεRI expression, we found that TGFβ1 suppresses TNF production independent of FcεRI levels. Rather, IgE-mediated signaling was altered. TGFβ1 significantly reduced expression of Fyn and Stat5, proteins critical for cytokine induction. These changes may partly explain the effects of TGFβ1, since Stat5B overexpression blocked TGF-mediated suppression of IgE-induced cytokine production. We also found that Stat5B is required for mast cell migration toward SCF, and that TGFβ1 reduced this migration. We found evidence that genetic background may alter TGF responses. TGFβ1 greatly reduced mast cell numbers in Th1-prone C57BL/6 but not Th2-prone 129/Sv mice. Furthermore, TGFβ1 did not suppress IgE-induced cytokine release, and increased c-Kit-mediated migration in 129/Sv mast cells. These data correlated with high basal Fyn and Stat5 expression in 129/Sv cells, which was not reduced by TGFβ1 treatment. Finally, primary human mast cell populations also showed variable sensitivity to TGFβ1-mediated changes in Stat5 and IgE-mediated IL-6 secretion. We propose that TGFβ1 regulates mast cell homeostasis, and that this feedback suppression may be dependent upon genetic context, predisposing some individuals to atopic disease.

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Section: Resultsmentioning

confidence: 99%

Genotype-Dependent Effects of TGF-β1 on Mast Cell Function: Targeting the Stat5 Pathway

Fernando

Faber

Pullen

et al. 2013

The Journal of Immunology

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“…Previous studies showed that activation of mast cells resulted in the rapid tyrosine phosphorylation of several transcription factors. We selected STAT5, which has been extensively studied in FcεRI-or KIT-activated cells (53,54), as the transcription factor. To elucidate the role of PAG in this process, we examined tyrosine phosphorylation of STAT5 in nonactivated and antigen-or SCF-activated PAG-WT and PAG-KO cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In SCF-activated cells, KIT activates STAT5 partly through the tyrosine kinase JAK2 (69). In contrast, JAK2 is dispensable in IgE-activated cells, which use FYN for STAT5 phosphorylation (53). Phosphorylated STAT5 serves as a transcription factor for a number of inflammatory genes (55).…”

Section: Discussionmentioning

confidence: 99%

Transmembrane Adaptor Protein PAG/CBP Is Involved in both Positive and Negative Regulation of Mast Cell Signaling

Dráberová

Potůčková

Hálová

et al. 2014

Molecular and Cellular Biology

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The transmembrane adaptor protein PAG/CBP (here, PAG) is expressed in multiple cell types. Tyrosine-phosphorylated PAG serves as an anchor for C-terminal SRC kinase, an inhibitor of SRC-family kinases. The role of PAG as a negative regulator of immunoreceptor signaling has been examined in several model systems, but no functions in vivo have been determined. Here, we examined the activation of bone marrow-derived mast cells (BMMCs) with PAG knockout and PAG knockdown and the corresponding controls. Our data show that PAG-deficient BMMCs exhibit impaired antigen-induced degranulation, extracellular calcium uptake, tyrosine phosphorylation of several key signaling proteins (including the high-affinity IgE receptor subunits, spleen tyrosine kinase, and phospholipase C), production of several cytokines and chemokines, and chemotaxis. The enzymatic activities of the LYN and FYN kinases were increased in nonactivated cells, suggesting the involvement of a LYN-and/or a FYNdependent negative regulatory loop. When BMMCs from PAG-knockout mice were activated via the KIT receptor, enhanced degranulation and tyrosine phosphorylation of the receptor were observed. In vivo experiments showed that PAG is a positive regulator of passive systemic anaphylaxis. The combined data indicate that PAG can function as both a positive and a negative regulator of mast cell signaling, depending upon the signaling pathway involved. Mast cells are widely distributed in the body, where they play important roles in innate as well as adaptive immune responses (1). To fulfill their role in adaptive immune responses, the cells express the high-affinity IgE receptor FcεRI on their plasma membranes. Aggregation of this tetrameric immunoreceptor, ␣␤␥2, induces cell signaling events leading to the release of preformed inflammatory mediators and the de novo synthesis and release of leukotrienes, cytokines, and chemokines. The first welldefined biochemical step after FcεRI triggering is tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motifs in the cytoplasmic tail of the FcεRI ␤ and ␥ subunits by the SRC family protein tyrosine kinase (PTK) LYN (2, 3). The phosphorylated ␤ and ␥ subunits then serve as binding and activation sites for LYN kinase and spleen tyrosine kinase (SYK), respectively. These two enzymes, together with FYN and other kinases, then phosphorylate various adaptor proteins and enzymes with a variety of functions in signal transduction pathways. The exact molecular events preceding LYN-mediated tyrosine phosphorylation of the FcεRI ␤ subunit are not clear, and several models have been proposed, including the transphosphorylation model (4), the lipid raft model (5), and the PTK-protein tyrosine phosphatase (PTP) interplay model (6).Our previous study with murine bone marrow-derived mast cells (BMMCs) showed that FcεRI triggering induced transient hyperphosphorylation of LYN kinase on its C-terminal regulatory tyrosine (Tyr 487), leading to the formation of a closed inactive conformation where the SRC homology 2 (...

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“…6A, 6B). Recently, the FynStat5B pathway has been reported to be a novel mechanism for FcεRI-mediated cytokine production (44). The marked suppression of FcεRI-mediated cytokine production may be due not only to reduced FcεRI expression, but also to reduced transcription factor Stat5B expression (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Transcription Factor Ehf Is Involved in TGF-β–Induced Suppression of FcεRI and c-Kit Expression and FcεRI-Mediated Activation in Mast Cells

Yamazaki

Nakano

Honjo

et al. 2015

The Journal of Immunology

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FcεRI, which is composed of α, β, and γ subunits, plays an important role in IgE-mediated allergic responses. TGF-β1 has been reported to suppress FcεRI and stem cell factor receptor c-Kit expression on mast cell surfaces and to suppress mast cell activation induced by cross-linking of FcεRI. However, the molecular mechanism by which these expressions and activation are suppressed by TGF-β1 remains unclear. In this study, we found that the expression of Ets homologous factor (Ehf), a member of the Ets family transcriptional factors, is upregulated by TGF-β/Smad signaling in mouse bone marrow–derived mast cells (BMMCs). Forced expression of Ehf in BMMCs repressed the transcription of genes encoding FcεRIα, FcεRIβ, and c-Kit, resulting in a reduction in cell surface FcεRI and c-Kit expression. Additionally, forced expression of Ehf suppressed FcεRI-mediated degranulation and cytokine production. Ehf inhibited the promoter activity of genes encoding FcεRIα, FcεRIβ, and c-Kit by binding to these gene promoters. Furthermore, the mRNA levels of Gata1, Gata2, and Stat5b were lower in BMMCs stably expressing Ehf compared with control cells. Because GATA-1 and GATA-2 are positive regulators of FcεRI and c-Kit expression, decreased expression of GATAs may be also involved in the reduction of FcεRI and c-Kit expression. Decreased expression of Stat5 may contribute to the suppression of cytokine production by BMMCs. In part, mast cell response to TGF-β1 was mimicked by forced expression of Ehf, suggesting that TGF-β1 suppresses FcεRI and c-Kit expression and suppresses FcεRI-mediated activation through upregulation of Ehf.

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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

Cited by 34 publications

References 42 publications

Genotype-Dependent Effects of TGF-β1 on Mast Cell Function: Targeting the Stat5 Pathway

Genotype-Dependent Effects of TGF-β1 on Mast Cell Function: Targeting the Stat5 Pathway

Transmembrane Adaptor Protein PAG/CBP Is Involved in both Positive and Negative Regulation of Mast Cell Signaling

The Transcription Factor Ehf Is Involved in TGF-β–Induced Suppression of FcεRI and c-Kit Expression and FcεRI-Mediated Activation in Mast Cells

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