The Four Distal Tyrosines Are Required for LAT-dependent Signaling in FcεRI-mediated Mast Cell Activation

Saitoh, Shin-Ichiroh; Odom, Sandra; Gomez, Gregorio; Sommers, Connie L.; Young, Howard A.; Rivera, Juan; Samelson, Lawrence E.

doi:10.1084/jem.20030574

Cited by 78 publications

(99 citation statements)

References 38 publications

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“…6, lines 2, 3, and 5). Similar results were recently found in LAT-deficient BMMCs reconstituted by tyrosine mutants of LAT (12). As suggested by data from the same investigation and from others conducted in T cells, LAT-dependent positive signals are thought to result from a cooperation between signaling molecules recruited by Y136, such as PLC-␥, and molecules recruited by the three distal tyrosines including Gads and Grb2 (25).…”

Section: Discussionsupporting

confidence: 74%

“…Therefore, LAT positively regulates Fc⑀RI signaling. A positive effect could be ascribed not only to the four distal tyrosines as previously reported (12), but also to the five proximal tyrosines. Biological responses of LAT-FFFF cells were indeed more intense than those of LAT Ϫ/Ϫ cells (Fig.…”

Section: Discussionsupporting

confidence: 61%

“…Fc⑀RI aggregation in bone marrow-derived mast cells (BMMCs) from LAT Ϫ/Ϫ mice triggered a reduced phosphorylation of SH2-containing leukocyte protein of 76 kDa and of PLC-␥, resulting in decreased Ca 2ϩ mobilization and MAPK activation and, ultimately, in a decreased release of preformed mediators and secretion of cytokines (7). A mutational analysis of the four distal tyrosines of LAT was recently performed in LAT Ϫ/Ϫ BMMCs reconstituted in vitro with wild-type (wt) or mutant LAT (12). This study confirmed that these residues are phosphorylated upon Fc⑀RI engagement and play a critical role for Fc⑀RI signaling by recruiting the same set of molecules in mast cells as in T cells.…”

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confidence: 99%

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Linker for Activation of T Cells Integrates Positive and Negative Signaling in Mast Cells

Malbec

Malissen

Isnardi

et al. 2004

The Journal of Immunology

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The transmembrane adapter linker for activation of T cells (LAT) is thought to couple immunoreceptors to intracellular signaling pathways. In mice, its intracytoplasmic domain contains nine tyrosines which, when phosphorylated upon receptor aggregation, recruit Src-homology 2 domain-containing cytosolic enzymes and adapters. The four distal tyrosines are critical for both TCR and FcεRI signaling. Unexpectedly, knock-in mice expressing LAT with a point mutation of the first or of the last three of these tyrosines exhibited an abnormal T cell development characterized by a massive expansion of TH2-like αβ or γδ T cells, respectively. This phenotype suggests that, besides positive signals, LAT might support negative signals that normally regulate terminal T cell differentiation and proliferation. We investigated here whether LAT might similarly regulate mast cell activation, by generating not only positive but also negative signals, following FcR engagement. To this end, we examined IgE- and/or IgG-induced secretory and intracellular responses of mast cells derived from knock-in mice expressing LAT with combinations of tyrosine mutations (Y136F, Y(175, 195, 235)F, or Y(136, 175, 195, 235)F). A systematic comparison of pairs of mutants enabled us to dissect the respective roles played by the five proximal and the four distal tyrosines. We found that LAT tyrosines differentially contribute to exocytosis and cytokine secretion and differentially regulate biological responses of mucosal- and serosal-type mast cells. We also found that, indeed, both positive and negative signals may emanate from distinct tyrosines in LAT, whose integration modulates mast cell secretory responses.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 61%

mentioning

confidence: 99%

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Linker for Activation of T Cells Integrates Positive and Negative Signaling in Mast Cells

Malbec

Malissen

Isnardi

et al. 2004

The Journal of Immunology

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“…Based on mutational analysis, one tyrosine was shown to recruit PLC-γ, and the three distal tyrosines Gads, Grap and Grb2. Similar results were obtained in T cells and mast cells [30]. LAT knock-in mice in which either the PLC-γ-binding tyrosine or the adapter-binding three distal tyrosines were mutated exhibited a polyclonal lymphoproliferation of CD4 + /TCRαβ or CD4 + /TCRγδ T cells, respectively, that secreted exaggerated levels of TH2 cytokines.…”

Section: Signaling Molecules In Negative Regulationsupporting

confidence: 81%

Regulation of allergy by Fc receptors

Bruhns

Frémont

Daëron

2005

Current Opinion in Immunology

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SummaryThe aggregation of high-affinity IgE receptors (FcεRI) on mast cells and basophils has long been known to be the critical event that initiates allergic reactions. Monomeric IgE was recently found to induce a variety of effects when binding to FcεRI. Up-regulation of FcεRI required binding only, whereas other responses resulted from FcεRI aggregation. Interestingly, FcεRI aggregation has been understood to generate a mixture of positive and negative intracellular signals. Mast cells/basophils express also low-affinity and, under specific conditions, high-affinity IgG receptors. When co-engaging these receptors with FcεRI, IgG antibodies can amplify or dampen IgE-induced mast cell activation. Based on these findings, FcRs have been proposed to be used as targets and/or tools for new therapeutic approaches of allergies.

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“…The two sets of binding sites also contribute to the recruitment of other molecules such as SLP-76 via Gads and they cooperate to stabilize the binding of molecules recruited by each other. A mutational analysis of the four distal tyrosines of LAT, in LAT -/-BMMC reconstituted in vitro with wt or mutant LAT (Saitoh et al, 2003), confirmed that, once phosphorylated upon FcεRI engagement, these residues play critical roles for FcεRI signaling by recruiting the same set of signaling molecules in mast cells as in T cells.…”

Section: Organization Of Fcr Signaling Complexes By Adapter Proteinsmentioning

confidence: 84%

Negative Signaling in Fc Receptor Complexes

Daëron

Lesourne

2006

Advances in Immunology

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Cell activation results from the transient displacement of an active balance between positive and negative signaling. This displacement depends in part on the engagement of cell surface receptors by extracellular ligands. Among these are Receptors for the Fc portion of immunoglobulins (FcRs). FcRs are widely expressed by cells of hematopoietic orign. When binding antibodies, FcRs provide these cells with immunoreceptors capable of triggering numerous biological responses in response to specific antigen. FcR-dependent cell activation is regulated by negative signals which are generated together with positive signals within signalosomes that form upon FcR engagement. Many molecules involved in positive signaling, including the FcRβ subunit, the src kinase lyn, the cytosolic adapter Grb2, the transmembrane adapters LAT and NTAL, are indeed also involved in negative signaling. A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1. Several layers of negative regulation operate sequentially as FcRs are engaged by extracellular ligands of increasing valency. A background protein tyrosine phosphatasedependent negative regulation maintains cells in a « resting » state. SHIP1-dependent negative regulation can be detected as soon as high-affinity FcRs are occupied by antibodies in the absence of antigen. It increases when activating FcRs are engaged by multivalent ligands and, further when FcR aggregation increases, accounting for the bell-shaped dose-response curve observed in excess of ligand. Finally, F-actin skeleton-associated high-molecular weight SHIP1, recruited to phopshorylated ITIMs, concentrates in signaling complexes when activating FcRs are coengaged with inhibitory FcRs by immune complexes. Based on these data, activating and inhibitory FcRs could be used for new therapeutic approaches of immune disorders.

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The Four Distal Tyrosines Are Required for LAT-dependent Signaling in FcεRI-mediated Mast Cell Activation

Cited by 78 publications

References 38 publications

Linker for Activation of T Cells Integrates Positive and Negative Signaling in Mast Cells

Linker for Activation of T Cells Integrates Positive and Negative Signaling in Mast Cells

Regulation of allergy by Fc receptors

Negative Signaling in Fc Receptor Complexes

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