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Overcoming the Signaling Defect of Lyn-Sequestering, Signal-Curtailing FcRI Dimers: Aggregated Dimers Can Dissociate from Lyn and Form Signaling Complexes with Syk¹

Martha Lara^*, Enrique Ortega^2,*, Israel Pecht, Janet R. Pfeiffer, A. Marina Martinez, Rebecca J. Lee, Zurab Surviladze, Bridget S. Wilson and Janet M. Oliver

^* Departamento de Inmunologia, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de Mexico, Mexico DF, Mexico; Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel; and Department of Pathology and Cancer Center, University of New Mexico School of Medicine, Albuquerque, NM 87131

Clustering the tetrameric (₂) IgE receptor, FcRI, on basophils and mast cells activates the Src-family tyrosine kinase, Lyn, which phosphorylates FcRI and subunit tyrosines, creating binding sites for the recruitment and activation of Syk. We reported previously that FcRI dimers formed by a particular anti-FcRI mAb (H10) initiate signaling through Lyn activation and FcRI subunit phosphorylation, but cause only modest activation of Syk and little Ca²⁺ mobilization and secretion. Curtailed signaling was linked to the formation of unusual, detergent-resistant complexes between Lyn and phosphorylated receptor subunits. Here, we show that H10-FcRI multimers, induced by adding F(ab')₂ of goat anti-mouse IgG to H10-treated cells, support strong Ca²⁺ mobilization and secretion. Accompanying the recovery of signaling, H10-FcRI multimers do not form stable complexes with Lyn and do support the phosphorylation of Syk and phospholipase C2. Immunogold electron microscopy showed that H10-FcRI dimers colocalize preferentially with Lyn and are rarely within the osmiophilic "signaling domains" that accumulate FcRI and Syk in Ag-treated cells. In contrast, H10-FcRI multimers frequently colocalize with Syk within osmiophilic patches. In sucrose gradient centrifugation analyses of detergent-extracted cells, H10-treated cells show a more complete redistribution of FcRI from heavy (detergent-soluble) to light (Lyn-enriched, detergent-resistant) fractions than cells activated with FcRI multimers. We hypothesize that restraints imposed by the particular orientation of H10-FcRI dimers traps them in signal-initiating Lyn microdomains, and that converting the dimers to multimers permits receptors to dissociate from Lyn and redistribute to separate membrane domains that support Syk-dependent signal propagation.

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