Non-T cell activation linker promotes mast cell survival by dampening the recruitment of SHIP1 by linker for activation of T cells.
The linker for activation of T cells (LAT) and the non-T cell activation linker (NTAL) are two transmembrane adapters which organize IgE receptor (FcepsilonRI) signaling complexes in mast cells. LAT positively regulates, whereas NTAL negatively regulates mast cell activation. We previously found that the four distal tyrosines of LAT can generate negative signals. We show here that two of these tyrosines provide two binding sites for SHIP1, that LAT recruits SHIP1 in vivo, and that SHIP1 recruitment is enhanced in NTAL-deficient cells. We show that NTAL negatively regulates mast cell activation by decreasing the recruitment, by LAT, of molecules involved in FcepsilonRI-dependent positive signaling. We show that NTAL also decreases the recruitment of SHIP1 by LAT, leading to an increased phosphorylation of the antiapoptotic molecule Akt, and positively regulates mast cell survival. We finally show that the positive effect of NTAL on Akt phosphorylation and mast cell survival requires LAT. Our data thus document the mechanisms by which LAT and NTAL can generate both positive and negative signals which differentially regulate mast cell activation and survival. They also provide molecular bases for the recruitment of SHIP1 in FcepsilonRI signaling complexes. SHIP1 is a major negative regulator of mast cell activation and, hence, of allergic reactions.
Roget
Karine
K
Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire, Paris, France.
Malissen
Marie
M
Malbec
Odile
O
Malissen
Bernard
B
Daëron
Marc
M
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D027182:Amino Acid Transport System y+ / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D027301:Fusion Regulatory Protein 1, Light Chains / Q000235:genetics / Q000502:physiology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D018909:src Homology Domains / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D027182:Amino Acid Transport System y+; D027301:Fusion Regulatory Protein 1, Light Chains; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D017455:Receptors, IgE; C420646:SLC7A8 protein, human; C518286:SLC7A8 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases