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The Journal of Immunology, 1999, 162: 176-185.
Copyright © 1999 by The American Association of Immunologists

Lyn Dissociation from Phosphorylated Fc{epsilon}RI Subunits: A New Regulatory Step in the Fc{epsilon}RI Signaling Cascade Revealed by Studies of Fc{epsilon}RI Dimer Signaling Activity1

Enrique Ortega*, Martha Lara*, Irene Lee*, Carla Santana*, A. Marina Martinez{dagger}, Janet R. Pfeiffer{dagger}, Rebecca J. Lee{dagger}, Bridget S. Wilson{dagger} and Janet M. Oliver2,{dagger}

* Departamento de Inmunologia, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico; and {dagger} Department of Pathology and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131

Cross-linking the heterotrimeric ({alpha}ß{gamma}2) IgE receptor, Fc{epsilon}RI, of mast cells activates two tyrosine kinases: Lyn, which phosphorylates ß and {gamma} subunit immunoreceptor tyrosine-based activation motifs, and Syk, which binds {gamma}-phospho-immunoreceptor tyrosine-based activation motifs and initiates cellular responses. We studied three Fc{epsilon}RI-dimerizing mAbs that maintain similar dispersed distributions over the surface of RBL-2H3 mast cells but elicit very different signaling responses. Specifically, mAb H10 receptor dimers induce very little inositol 1,4,5-trisphosphate synthesis, Ca2+ mobilization, secretion, spreading, ruffling, and actin plaque assembly, whereas dimers generated with the other anti-Fc{epsilon}RI mAbs induce responses that are only modestly lower than that to multivalent Ag. H10 receptor dimers activate Lyn and support Fc{epsilon}RI ß and {gamma} subunit phosphorylation but are poor Syk activators compared with Ag and the other anti-Fc{epsilon}RI mAbs. H10 receptor dimers have two other distinguishing features. First, they induce stable complexes between activated Lyn and receptor subunits. Second, the predominant Lyn-binding phospho-ß isoform found in mAb H10-treated cells is a less tyrosine phosphorylated, more electrophoretically mobile species than the predominant isoform in Ag-treated cells that does not coprecipitate with Lyn. These studies implicate Lyn dissociation from highly phosphorylated receptor subunits as a new regulatory step in the Fc{epsilon}RI signaling cascade required for Syk activation and signal progression.




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