Calcineurin–Rcan1 Interaction Contributes to Stem Cell Factor–Mediated Mast Cell Activation

Wu, Zhengli; Li, Yanhong; MacNeil, Adam J.; Junkins, Robert D.; Berman, Jason N.; Lin, Tong‐Jun

doi:10.4049/jimmunol.1301271

Cited by 17 publications

(12 citation statements)

References 41 publications

(55 reference statements)

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“…Evidence shows that several pathways that are important in normal stem cells (BCL2 family genes, Notch, Sonic hedgehog and Wnt signaling pathways), may also act in cancer development [69] , [70] . For instance, we saw the highest level of antiapoptotic BCL2 and BCL2A1 and stem cell factor inducer [71] RCAN1 expression level in MC when compared to KC, FB and the whole skin ( S2 Table ). Interestingly, CD200 was uniquely expressed in MC ( Table 2 ).…”

Section: Resultsmentioning

confidence: 97%

Melanocytes in the Skin – Comparative Whole Transcriptome Analysis of Main Skin Cell Types

et al. 2014

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Melanocytes possess several functions besides a role in pigment synthesis, but detailed characteristics of the cells are still unclear. We used whole transcriptome sequencing (RNA-Seq) to assess differential gene expression of cultivated normal human melanocytes with respect to keratinocytes, fibroblasts and whole skin. The present results reveal cultivated melanocytes as highly proliferative cells with possible stem cell-like properties. The enhanced readiness to regenerate makes melanocytes the most vulnerable cells in the skin and explains their high risk of developing into malignant melanoma.

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Section: Resultsmentioning

confidence: 97%

Melanocytes in the Skin – Comparative Whole Transcriptome Analysis of Main Skin Cell Types

et al. 2014

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“…Previous studies using experimental anaphylaxis in Rcan1-deficient mice have found a role for Rcan1 in regulating Fc-εRI-mediated signaling and mast-cell function ( 62 ). Rcan1 −/− bone-marrow-derived mast cells show increased transcriptional activation of NF-κB and NFAT and calcineurin activity following stem-cell factor stimulation ( 63 ). On the other hand, Rcan1 seems to be required for the development of pulmonary eosinophilia in allergic inflammation in mice ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis

et al. 2017

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Anaphylaxis, the most serious and life-threatening allergic reaction, produces the release of inflammatory mediators by mast cells and basophils. Regulator of calcineurin 1 (Rcan1) is a negative regulator of mast-cell degranulation. The action of mediators leads to vasodilation and an increase in vascular permeability, causing great loss of intravascular volume in a short time. Nevertheless, the molecular basis remains unexplored on the vascular level. We investigated Rcan1 expression induced by histamine, platelet-activating factor (PAF), and epinephrine in primary human vein (HV)-/artery (HA)-derived endothelial cells (ECs) and human dermal microvascular ECs (HMVEC-D). Vascular permeability was analyzed in vitro in human ECs with forced Rcan1 expression using Transwell migration assays and in vivo using Rcan1 knockout mice. Histamine, but neither PAF nor epinephrine, induced Rcan1-4 mRNA and protein expression in primary HV-ECs, HA-ECs, and HMVEC-D through histamine receptor 1 (H1R). These effects were prevented by pharmacological inhibition of calcineurin with cyclosporine A. Moreover, intravenous histamine administration increased Rcan1 expression in lung tissues of mice undergoing experimental anaphylaxis. Functional in vitro assays showed that overexpression of Rcan1 promotes barrier integrity, suggesting a role played by this molecule in vascular permeability. Consistent with these findings, in vivo models of subcutaneous and intravenous histamine-mediated fluid extravasation showed increased response in skin, aorta, and lungs of Rcan1-deficient mice compared with wild-type animals. These findings reveal that endothelial Rcan1 is synthesized in response to histamine through a calcineurin-sensitive pathway and may reduce barrier breakdown, thus contributing to the strengthening of the endothelium and resistance to anaphylaxis. These new insights underscore its potential role as a regulator of sensitivity to anaphylaxis in humans.

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“…In a later paper, the same group reported that SCF induces IκBα phosphorylation but not degradation in BMMCs which is in accordance with our data. The reason for these different findings remains unknown [ 52 , 53 ]. We consistently found IκBα phosphorylation without degradation upon stimulation with SCF.…”

Section: Discussionmentioning

confidence: 99%

TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases

et al. 2015

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NF-κB activation depends on the IKK complex consisting of the catalytically active IKK1 and 2 subunits and the scaffold protein NEMO. Hitherto, IKK2 activation has always been associated with IκBα degradation, NF-κB activation, and cytokine production. In contrast, we found that in SCF-stimulated primary bone marrow-derived mast cells (BMMCs), IKK2 is alternatively activated. Mechanistically, activated TAK1 mediates the association between c-Kit and IKK2 and therefore facilitates the Lyn-dependent IKK2 activation which suffices to mediate mitogenic signaling but, surprisingly, does not result in NF-κB activation. Moreover, the c-Kit-mediated and Lyn-dependent IKK2 activation is targeted by MyD88-dependent pathways leading to enhanced IKK2 activation and therefore to potentiated effector functions. In neoplastic cells, expressing constitutively active c-Kit mutants, activated TAK1 and IKKs do also not induce NF-κB activation but mediate uncontrolled proliferation, resistance to apoptosis and enables IL-33 to mediate c-Kit-dependent signaling. Together, we identified the formation of the c-Kit-Lyn-TAK1 signalosome which mediates IKK2 activation. Unexpectedly, this IKK activation is uncoupled from the NF-κB-machinery but is critical to modulate functional cell responses in primary-, and mediates uncontrolled proliferation and survival of tumor-mast cells. Therefore, targeting TAK1 and IKKs might be a novel approach to treat c-Kit-driven diseases.

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Calcineurin–Rcan1 Interaction Contributes to Stem Cell Factor–Mediated Mast Cell Activation

Cited by 17 publications

References 41 publications

Melanocytes in the Skin – Comparative Whole Transcriptome Analysis of Main Skin Cell Types

Melanocytes in the Skin – Comparative Whole Transcriptome Analysis of Main Skin Cell Types

Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis

TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases

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