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Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Little is known about the signals downstream of PI3K which regulate mast cell homeostasis and function following Fc
RI aggregation and Kit ligation. In this study, we investigated the role of the mammalian target of rapamycin complex 1 (mTORC1) pathway in these responses. In human and mouse mast cells, stimulation via FcRI or Kit resulted in a marked PI3K-dependent activation of the mTORC1 pathway, as revealed by the wortmannin-sensitive sequential phosphorylation of tuberin, mTOR, p70S6 kinase (p70S6K), and 4E-BP1. In contrast, in human tumor mast cells, the mTORC1 pathway was constitutively activated and this was associated with markedly elevated levels of mTORC1 pathway components. Rapamycin, a specific inhibitor of mTORC1, selectively and completely blocked the FcRI- and Kit-induced mTORC1-dependent p70S6K phosphorylation and partially blocked the 4E-BP1 phosphorylation. In parallel, although rapamycin had no effect on FcRI-mediated degranulation or Kit-mediated cell adhesion, it inhibited cytokine production, and kit-mediated chemotaxis and cell survival. Furthermore, Rapamycin also blocked the constitutive activation of the mTORC1 pathway and inhibited cell survival of tumor mast cells. These data provide evidence that mTORC1 is a point of divergency for the PI3K-regulated downstream events of FcRI and Kit for the selective regulation of mast cell functions. Specifically, the mTORC1 pathway may play a critical role in normal and dysregulated control of mast cell homeostasis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research within the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Alasdair M. Gilfillan, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11C206, 10 Center Drive MSC 1881, Bethesda, MD 20892. E-mail address: agilfillan{at}niaid.nih.gov
3 Abbreviations used in this paper: SCF, stem cell factor; FcRI, high affinity IgE receptor; PH, pleckstrin homology; PL, phospholipase; mTOR, mammarian target of rapamycin; mTORC1, mTOR complex 1; p70S6K, p70 ribosomal S6 kinase; 4E-BP1, eukaryotic initiation factor 4E-binding protein 1; HuMCs, CD34+-derived cultured human mast cells; BMMC, bone marrow-derived mast cell; SA, streptavidin; DNP, dinitrophenyl; β-hex, β-hexosaminidase.
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