COMPARTMENTALIZED ACTIVATION OF THE HIGH-AFFINITY IMMUNOGLOBULIN-E RECEPTOR WITHIN MEMBRANE DOMAINS

The earliest known step in the activation of the high affinity IgE rec eptor, Fc epsilon RI, is the tyrosine phosphorylation of its beta and gamma subunits by the Src family tyrosine kinase, Lyn. We report here that aggregation-dependent association of Fc epsilon RI with specializ ed regions of the plasma membrane precedes its tyrosine phosphorylatio n and appears necessary for this event. Tyrosine phosphorylation of be ta and gamma occurs in intact cells only for Fc epsilon RI that associ ate with these detergent-resistant membrane domains, which are enriche d in active Lyn. Furthermore, efficient in vitro tyrosine phosphorylat ion of Fc epsilon RI subunits occurs only for those associated with is olated domains. This association and in vitro phosphorylation are high ly sensitive to low concentrations of detergent, suggesting that lipid -mediated interactions with Lyn are important in Fc epsilon RI activat ion, Participation of membrane domains accounts for previously unexpla ined aspects of Fc epsilon RI-mediated signaling and may be relevant t o signaling by other multichain immune receptors.