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,
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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 (Fc
RI) 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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