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《Nature Immunology》：让过敏“暂停”
Published online: 04 July 2004; | doi:10.1038/ni1093
RabGEF1 is a negative regulator of mast cell activation and skin inflammation
See-Ying Tam1, Mindy Tsai1, John N Snouwaert2, Janet Kalesnikoff1, Didier Scherrer1, 4, Susumu Nakae1, Devavani Chatterjea1, Donna M Bouley3 & Stephen J Galli1
1 Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
2 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
3 Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
4 Present address: Entelos, Foster City, California 94404, USA.
Correspondence should be addressed to See-Ying Tam stam@stanford.edu or Stephen J Galli sgalli@stanford.edu
Mast cell activation induced by aggregation of FcRI receptors with immunoglobulin E and antigen is mediated through the activation of multiple protein kinase cascades. Here we report that the regulatory protein RabGEF1 bound to Ras and negatively regulated Ras activation and its 'downstream' effector pathways in FcRI-dependent mast cell activation. RabGEF1-deficient mast cells showed enhanced degranulation and release of lipid mediators and cytokines in response to FcRI aggregation. RabGEF1-deficient mice developed severe skin inflammation and had increased numbers of mast cells. Thus, RabGEF1 is a negative regulator of FcRI-dependent mast cell activation, and a lack of RabGEF1 results in the development of skin inflammation in vivo.
Mast cells are chief effector cells in immunoglobulin E (IgE)–associated and T helper 2 type cell–dependent immediate hypersensitivity reactions and allergic diseases, as well as in certain innate immune responses1, 2, 3, 4, 5, 6, 7, 8. Aggregation of the high-affinity IgE receptors (FcRI) expressed on mast cells by binding of multivalent antigen to FcRI-bound IgE molecules initiates mast cell activation. This activation leads to degranulation, with the secretion of preformed mediators such as histamine; the synthesis and release of lipid mediators, including prostaglandin D2 (PGD2) and leukotriene C4 (LTC4); and the secretion of many cytokines1, 3, 5, 7, 8. The synthesis and release of lipid mediators and cytokines in response to FcRI aggregation are mediated through signaling pathways that involve Ras activation and Ras-mediated protein kinase cascades9, 10, 11, 12, 13, 14.
Ras proteins are small GTP-binding proteins important in the control of cell activation, proliferation and differentiation in diverse cell types. Conversion of the inactive GDP-bound Ras to the active GTP-bound state (for example, when Ras guanine nucleotide–exchange factors (GEFs) are recruited to the plasma membrane in response to an appropriate extracellular signal) relays responses initiated at the cell surface to multiple downstream signaling cascades. Ras can bind directly to the key effector Raf-1 to initiate activation of the ERK mitogen-activated protein (MAP) kinase cascade15. However, Ras regulates a wide spectrum of cellular responses, and multiple effectors are required to mediate the many potential biological actions of Ras. Indeed, a diverse group of structurally and functionally distinct candidate Ras effectors in addition to Raf-1 have been identified, including GEFs for Ral, Ras GTPase-activating proteins (GAPs) such as p120 GAP and neurofibromin, MEK kinase 1, AF6, phosphatidylinositol-3-kinase and Ras–interaction-interference 1 (RIN1)15, 16.
In mast cells, the activation of Ras-mediated protein kinase cascades is required for optimal mediator release when cell activation is initiated by antigen- and IgE-dependent aggregation of FcRI (refs. 9, 10, 11, 12, 13, 14). FcRI is a heterotetrameric receptor consisting of one -subunit that binds to the Fc portion of IgE, one -subunit that functions as a signal amplifier and two -subunits that can transmit signals into the cell1, 3. Aggregation of FcRI activates Lyn, a Src family protein-tyrosine kinase that is constitutively associated with the -subunit17, 18. Activated Lyn then phosphorylates the immunoreceptor tyrosine–based activation motifs of the - and -subunits, inducing the recruitment and activation of Syk19, 20, which phosphorylates multiple substrates, including the linker for activation of T cells21 and phospholipase C-. This results in the activation of two downstream cascades: the phospholipase C-–protein kinase C cascade, required for degranulation and the release of mediators stored in the cells' cytoplasmic granules, and the Ras–ERK–phospholipase A2 cascade, critical for the release of cytokines and arachidonic acid9, 10, 11, 12, 13, 14, 22
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作者:admin@医学,生命科学 2011-04-02 05:14
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