The Fyn-STAT5 Pathway: A New Frontier in IgE- and IgG-Mediated Mast Cell Signaling

Pullen, Nick; Falanga, Yves T.; Morales, Johanna K.; Ryan, John

doi:10.3389/fimmu.2012.00117

Cited by 28 publications

(27 citation statements)

References 134 publications

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“…Moreover, TGFβ1 has many direct effects on mast cells, including increased mMCP-1, and -7 expression, enhanced adhesion and increased migration. However, we and others have also noted that TGFβ1 has suppressive activities on mast cells, including decreased proliferation, FcεRI expression, cytokine production, and reduced c-Kit expression, which some correlated with the induction of apoptosis (reviewed in (46) and (16). How these suppressive activities are carried out has not been determined.…”

Section: Discussionmentioning

confidence: 79%

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: Discussionmentioning

confidence: 79%

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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“…The decreased phosphorylation of STAT5 in antigen-stimulated PAG-KO cells suggested the reduced production of cytokines and chemokines in such cells (55). Detailed analysis at the protein and mRNA levels showed that, indeed, the levels of three selected cytokines, TNF-␣, IL-6, and IL-13, were significantly reduced in antigenstimulated PAG-KO cells compared with their levels in PAG-WT cells at both the protein and mRNA levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…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). The reduced transcription of genes for cytokines (TNF-␣, IL-6, and IL-13) and chemokines (CCL3 and CCL4) and the reduced production of TNF-␣, IL-6, and IL-13 in antigenactivated PAG-KO cells could be a direct consequence of impaired STAT5 tyrosine phosphorylation.…”

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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“…In our study, ruxolitinib clearly inhibited MC activity, but its exact intracellular mechanism is not fully elucidated yet. JAK2, and subsequently STAT5, are situated downstream of KIT in MC, and thereby involved in the proliferation and survival of MC . The involvement of the JAK2‐STAT5 pathway in MC degranulation is less well‐described, although there is some evidence available.…”

Section: Discussionmentioning

confidence: 99%

“…Of the different JAK‐ and STAT molecules and signaling pathways currently known, the JAK2‐STAT5 pathway is considered the most important for growth and survival of MC . STAT5 also plays a role in IgE‐mediated MC degranulation, rendering the JAK2‐STAT5 pathway an interesting target for the inhibition of MC activation . In support of this, it has previously been shown that the JAK1/JAK2 inhibitor ruxolitinib attenuates ovalbumin‐induced passive systemic anaphylaxis in mice, while another study demonstrated that several JAK2‐ and STAT5‐inhibitors were able to inhibit activation of canine mastocytoma cell lines .…”

Section: Introductionmentioning

confidence: 89%

The JAK1/JAK2‐ inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release

Hermans

Schrijver

Holten-Neelen

et al. 2018

Clin Experimental Allergy

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The Fyn-STAT5 Pathway: A New Frontier in IgE- and IgG-Mediated Mast Cell Signaling

Cited by 28 publications

References 134 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 JAK1/JAK2‐ inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release

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