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Differential Interaction of Crkl with Cbl or C3G, Hef-1, and Subunit Immunoreceptor Tyrosine-Based Activation Motif in Signaling of Myeloid High Affinity Fc Receptor for IgG (FcRI)¹

Wade T. Kyono^*, Ron de Jong, Rae Kil Park, Yenbou Liu^*, Nora Heisterkamp, John Groffen and Donald L. Durden^2,*

^* Neil Bogart Memorial Laboratories, Division of Hematology-Oncology, and Section of Molecular Carcinogenesis, Department of Pathology, Childrens Hospital Los Angeles Research Institute and University of Southern California School of Medicine, Los Angeles, CA 90027; and Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan Jeonbuk, Korea

Cbl-Crkl and Crkl-C3G interactions have been implicated in T cell and B cell receptor signaling and in the regulation of the small GTPase, Rap1. Recent evidence suggests that Rap1 plays a prominent role in the regulation of immunoreceptor tyrosine-based activation motif (ITAM) signaling. To gain insight into the role of Crkl in myeloid ITAM signaling, we investigated Cbl-Crkl and Crkl-C3G interactions following FcRI aggregation in U937IF cells. FcRI cross-linking of U937IF cells results in the tyrosine phosphorylation of Cbl, Crkl, and Hef-1, an increase in the association of Crkl with Cbl via direct SH2 domain interaction and increased Crkl-Hef-1 binding. Crkl constitutively binds to the guanine nucleotide-releasing protein, C3G, via direct SH3 domain binding. Our data show that distinct Cbl-Crkl and Crkl-C3G complexes exist in myeloid cells, suggesting that these complexes may modulate distinct signaling events. Anti-Crkl immunoprecipitations demonstrate that the ITAM-containing subunit of FcRI is induced to form a complex with the Crkl protein, and Crkl binds to the cytoskeletal protein, Hef-1. The induced association of Crkl with Cbl, Hef-1, and FcRI after FcRI activation and the constitutive association between C3G and Crkl provide the first evidence that a FcRI-Crkl-C3G complex may link ITAM receptors to the activation of Rap1 in myeloid cells.