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High Affinity IgG Receptor Activation of Src Family Kinases Is Required for Modulation of the Shc-Grb2-Sos Complex and the Downstream Activation of the Nicotinamide Adenine Dinucleotide Phosphate (Reduced) Oxidase¹

Rae-Kil Park^,, Anat Erdreich-Epstein, Ming Liu, Kayvon D. Izadi^* and Donald L. Durden^2,*

^* Herman B. Wells Center for Pediatric Research, Department of Pediatrics and Biochemistry, Indiana University School of Medicine, Indianapolis, IN 46202; Childrens Hospital, Los Angeles Research Institute, Los Angeles, CA 90027; and Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan Jeonbuk, Korea

We used the U937 cell line to examine the modulation of adaptor protein interactions (Shc, Grb2, and Cbl) after high affinity IgG receptor (FcRI) cross-linking, leading to the formation of the Grb2-Sos complex, the activation of Ras, and the regulation of the respiratory burst. Cross-linking of FcRI induced the conversion of GDP-Ras to GTP-Ras reaching a maximum 5 min after stimulation. Concomitant with Ras activation, Sos underwent an electrophoretic mobility shift and the Sos-Grb2 association was increased (6-fold). The Grb2-Sos complex was present only in the membrane fraction and was augmented after FcRI stimulation. Tyrosine-phosphorylated Shc, mainly the p52 isoform, was observed to transiently onload to the membrane Grb2-Sos complex on FcRI stimulation. Cross-linking of FcRI induces the tyrosine phosphorylation of Cbl, which forms a complex with Grb2 and Shc via the Cbl C terminus. Kinetic experiments confirm that Cbl-Grb2 is relatively stable, whereas Grb2-Sos, Grb2-Shc, and Cbl-Shc interactions are highly inducible. The Src family tyrosine kinase inhibitor, PP1, was shown to completely inhibit Shc tyrosine phosphorylation, the Shc-Grb2 interaction, and the FcR-induced respiratory burst. Our results provide the first evidence that the upstream activation of Src kinases is required for the modulation of the Shc-Grb2 interaction and the myeloid NADPH oxidase response.

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