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*
Neil Bogart Memorial Laboratories, Division of Hematology-Oncology, Children’s Hospital Los Angeles Research Institute and University of Southern California School of Medicine, Norris Cancer Center, Los Angeles, CA 90027; and
Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Korea
In this study, we provide the first evidence for role of the CBL
adapter protein interaction in Fc
RI receptor signal transduction. We
study the FcRI receptor, an immunoreceptor tyrosine activation motif
(ITAM)-linked signaling pathway, using IFN--differentiated U937
myeloid cells, termed U937IF cells. CBL is constitutively associated
with both GRB2 and the ITAM-containing receptor subunit, FcRI of
FcRI, providing direct evidence that CBL functions in myeloid ITAM
signaling. FcRI cross-linking of U937IF cells induces the tyrosine
phosphorylation of CBL that is associated with an altered CBL-GRB2
interaction. Both GRB2-SH3 and SH2 domains bind CBL in resting cell
lysates; upon FcRI stimulation, phosphorylated CBL binds exclusively
to the GRB2-SH2 domain. Glutathione-S-transferase fusion protein data
demonstrate that the constitutive interaction of CBL with GRB2 and CRKL
is mediated via two discrete regions of the CBL C terminus. The
proximal C terminus (residues 461–670) binds to GRB2 constitutively,
and under conditions of receptor activation binds to the
tyrosine-phosphorylated SHC adapter molecule. The distal C terminus of
CBL (residues 671–906) binds the CRKL adapter protein. The data
demonstrate that the CBL-GRB2 and GRB2-SOS protein complexes are
distinct and mutually exclusive in U937IF cells, supporting a model by
which the CBL-GRB2 and GRB2-SOS complexes function in separate pathways
for myeloid FcRI signaling.
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