Compartmentalized activation of the high affinity immunoglobulin E receptor within membrane domains

Abstract

The earliest known step in the activation of the high affinity IgE receptor, FcεRI, is the tyrosine phosphorylation of its β and y subunits by the Src family tyrosine kinase, Lyn. We report here that aggregation- dependent association of FcεRI with specialized regions of the plasma membrane precedes its tyrosine phosphorylation and appears necessary for this event. Tyrosine phosphorylation of β and y occurs in intact cells only for FcεRI that associate with these detergent-resistant membrane domains, which are enriched in active Lyn. Furthermore, efficient in vitro tyrosine phosphorylation of FcεRI subunits occurs only for those associated with isolated domains. This association and in vitro phosphorylation are highly sensitive to low concentrations of detergent, suggesting that lipid-mediated interactions with Lyn are important in FcεRI activation. Participation of membrane domains accounts for previously unexplained aspects of FcεRI- mediated signaling and may be relevant to signaling by other multichain immune receptors.