Mast cells play a central role in type I hypersensitivity reactions and allergic disorders such as anaphylaxis and asthma. Activation of mast cells, through a cascade of phosphorylation events, leads to the release of mediators of the early phase allergic response. Understanding the molecular architecture underlying mast cell signaling may provide possibilities for therapeutic intervention in asthma and other allergic diseases. Although many details of mast cell signaling have been described previously, a systematic, quantitative analysis of the global tyrosine phosphorylation events that are triggered by activation of the mast cell receptor is lacking. In many cases, the involvement of particular proteins in mast cell signaling has been established generally, but the precise molecular mechanism of the interaction between known signaling proteins often mediated through phosphorylation is still obscure. Using recently advanced methodologies in mass spectrometry, including automation of phosphopeptide enrichments and detection, we have now substantially characterized, with temporal resolution as short as 10 s, the sites and levels of tyrosine phosphorylation across 10 min of FcRI-induced mast cell activation. These results reveal a far more extensive array of tyrosine phosphorylation events than previously known, including novel phosphorylation sites on canonical mast cell signaling molecules, as well as unexpected pathway components downstream of FcRI activation. M ast cells are regarded as crucial effector cells in allergic reactions and IgE-associated immune responses(1). Activation of mast cells, a critical feature of type I hypersensitive reactions, leads to the release of a wide range of chemical mediators and cytokines that recruit inflammatory cells and regulate inflammatory responses, such as mucus secretion, vasodilation, and bronchoconstriction (2). During activation, the mast cell high-affinity IgE receptor FcRI is cross-linked by allergens through bound IgE, leading to a cascade of signaling events and the release of preformed inflammatory mediators localized in specialized granules, the de novo synthesis and secretion of proinflammatory lipid mediators, and the synthesis and secretion of cytokines and chemokines (3).Some aspects of FcRI-mediated mast cell activation and inhibition pathways have been described previously (4) (Fig. 1). FcRI expressed on mast cells is comprised of three subunits: an IgEbinding ␣ subunit, a signal-amplifying  subunit, and two disulfide-linked signal-initiating ␥ subunits (5). Following FcRI aggregation, the activation of  subunit-bound protein tyrosine kinase Lyn and, subsequently, tyrosine phosphorylation of ITAM regions in the  and ␥ subunits of FcRI, initiates a complex series of intracellular signaling events (6 -10). Phosphorylated ITAMs provide docking sites for Src homology 2 (SH2) 3 domain-containing cytoplasmic tyrosine kinases such as Syk (11), Lyn, and Fyn (12), leading to the activation of Syk (11). The subsequent phosphorylation of linker for activation ...
KLRG1 is an inhibitory receptor expressed on a subset of mature T and NK cells. Recently, E-, N-, and R-cadherin have been identified as ligands for KLRG1. Cadherins are a large family of transmembrane or membrane-associated glycoproteins that were thought to only bind specifically to other cadherins to mediate specific cell-to-cell adhesion in a Ca 2؉ -dependent manner. The consequences of cadherin KLRG1 molecular interactions are not well characterized. Here, we report that the first 2 extracellular domains of cadherin are sufficient to initiate a KLRG1-dependent signaling. We also demonstrate that KLRG1 engagement inhibits cadherin-dependent cellular adhesion and influences dendritic cell secretion of inflammatory cytokines, thereby exerting immunosuppressive effects. Consistent with this, engagement of cadherin by KLRG1 molecule induces cadherin tyrosine phosphorylation. Therefore, KLRG1/cadherin interaction leads to the generation of a bidirectional signal in which both KLRG1 and cadherin activate downstream signaling cascades simultaneously. Taken IntroductionEpithelial cadherins (E-cadherins), neural cadherins (N-cadherins), and retinal cadherins (R-cadherins) are part of the classical cadherins. These ubiquitously expressed cell adhesion molecules are a large family of transmembrane or membrane-associated glycoproteins comprising an extracellular domain containing 5 cadherin repeats (EC1-5) responsible for cell-to-cell interactions, a transmembrane domain, and a cytoplasmic domain that is linked to the actin cytoskeleton. Typically, cadherins mediate calciumdependent homophilic adhesion, thereby promoting association of cells expressing the same cadherin family members to form adherens junctions. 1,2 The formation of adherens junctions is dependent on the association of cadherin's cytoplasmic tail with -catenin and its partners. 1 Numerous biologic processes, including homeostasis and embryogenesis, rely on the selective adherence of one adhesion molecule to another through precise intermolecular interactions. 3 The spatiotemporal regulation of cadherin expression and function are vital to tissue morphogenesis, providing a basis for the formation of epithelial layers of the skin and intestine. [4][5][6] Aside from their homophilic adhesion mode, E-, N-, and R-cadherins have been recently reported to bind in a heterophilic manner with killer cell lectin-like receptor G1 (KLRG1). [7][8][9] KLRG1 is a transmembrane inhibitory receptor belonging to the C-type lectin-like superfamily that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. The molecule was first identified in the rat basophilic leukemia cell line RBL-2H3 and was originally termed mast cell function-associated Ag (MAFA). [10][11][12][13][14][15] In mice and humans, this well-conserved receptor is found on subsets of T and natural killer (NK) cells. [16][17][18][19][20][21][22][23][24] Cells that express KLRG1 include the most mature and recently activated NK cells as well as effector/memory T cells. [...
The SH2-containing inositol phosphatase-1 (SHIP-1) is a 5 inositol phosphatase known to negatively regulate the product of phosphoinositide-3 kinase (PI3K), phosphatidylinositol-3.4,5-trisphosphate. SHIP-1 can be recruited to a large number of inhibitory receptors expressed on natural killer (NK) cells. However, its role in NK cell development, maturation, and functions is not well defined. In this study, we found that the absence of SHIP-1 results in a loss of peripheral NK cells. However, using chimeric mice we demonstrated that SHIP-1 expression is not required intrinsically for NK cell lineage development. In contrast, SHIP-1 is required cell autonomously for NK cell terminal differentiation. These findings reveal both a direct and indirect role for SHIP-1 at different NK cell development checkpoints. Notably, SHIP-1-deficient NK cells display an impaired ability to secrete IFN-␥ during cytokine receptor-mediated responses, whereas immunoreceptor tyrosine-based activation motif containing receptor-mediated responses is not affected. Taken IntroductionNatural killer (NK) cells are large granular lymphocytes with a critical role in innate immunity and are important in orchestrating the adaptive immune system. 1,2 Their ability to produce immunoregulatory cytokines, such as interferon (IFN)-␥, and release perforin and granzymes is crucial for tumor immunosurveillance and elimination of pathogens. 3 These NK effector functions are dependent on the integration of signals delivered from a variety of activating and inhibitory receptors on interaction with neighboring cells. 4 Significant progress has been made on the regulation of receptor and target recognition as well as identification of signals transduced for NK cell action. However, evidence for how these signaling molecules, specifically phosphatases, might govern NK cell development and thereby influence their effector function has been lacking. A better understanding of the mechanisms that govern NK cell development into functional effector cells is crucial to demystifying disease processes and fully utilizing NK cells as therapeutic agents.The bone marrow (BM) is the main site for NK cell development. An intact BM microenvironment provides NK cells with both cellular substrates and signals required from several stromal factors to sustain cell proliferation and differentiation. 1 NK cell precursors (NKPs) in the BM are derived from hematopoietic stem cells that give rise to immature NK (iNK) cells and mature NK (mNK) cells. 5 mNK cells egress from the BM and represent the main NK cell population in the peripheral lymphoid organs, such as the spleen. The NK cell maturation process in the BM has been well characterized based on the differential acquisition of NK cell receptors and the achievement of their full effector functions. 1,6,7 The acquisition of both activating and inhibitory receptors results in the ability of NK cells to recognize and kill target cells with minimal damage to the host. On NK cell synapse formation, appropriate downstream signaling ...
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