CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling

Rae Kil Park, Wade T. Kyono, Yenbou Liu, Donald L. Durden

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

In this study, we provide the first evidence for role of the CBL adapter protein interaction in FcγRI receptor signal transduction. We study the FcγRI receptor, an immunoreceptor tyrosine activation motif (ITAM)-linked signaling pathway, using IFN-γ-differentiated U937 myeloid cells, termed U937IF cells. CBL is constitutively associated with both GRB2 and the ITAM- containing receptor subunit, FcγRIγ, of FcγRI, providing direct evidence that CBL functions in myeloid ITAM signaling. FcyRI 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 FcγRI 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 CBLGRB2 and GRB2-SOS complexes function in separate pathways for myeloid FcγRI signaling.

Original languageEnglish (US)
Pages (from-to)5018-5027
Number of pages10
JournalJournal of Immunology
Volume160
Issue number10
StatePublished - May 15 1998

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Park, R. K., Kyono, W. T., Liu, Y., & Durden, D. L. (1998). CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling. Journal of Immunology, 160(10), 5018-5027.