Co-clustering of Fcγ and B cell receptors induces dephosphorylation of the Grb2-associated binder 1 docking protein

Gábor Koncz, Gábor K. Tóth, Gyöngyi Bökönyi, György Kéri, Israel Pecht, David Medgyesi, János Gergely, Gabriella Sármay

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The immunoreceptor tyrosine-based inhibitory motif (ITIM) of human type IIb Fcγ receptor (FcγRIIb) is phosphorylated on its tyrosine upon co-clustering with the B cell receptor (BCR). The phosphorylated ITIM (p-ITIM) binds to the SH2 domains of polyphosphoinositol 5-phosphatase (SHIP) and the tyrosine phosphatase, SHP-2. We investigated the involvement of the molecular complex composed of the phosphorylated SHIP and FcγRIIb in the activation of SHP-2. As a model compound, we synthesized a bisphosphopeptide, combining the sequences of p-ITIM and the N-terminal tyrosine phosphorylated motif of SHIP with a flexible spacer. This compound bound to the recombinant SH2 domains of SHP-2 with high affinity and activated the phosphatase in an in vitro assay. These data suggest that the phosphorylated FcγRII-SHIP complexes formed in the intact cells may also activate SHP-2. Grb2-associated binder 1 (Gab1) is a multisite docking protein, which becomes tyrosine-phosphorylated in response to various types of signaling, including BCR. In turn it binds to the SH2 domains of SHP-2, SHIP and the p85 subunit of phosphatidyl inositol 3-kinase (PtdIns3-K) and may regulate their activity. Gab1 is a potential substrate of SHP-2, thus its binding to FcγRIIb may modify the Gab1-bound signaling complex. We show here that Gab1 is part of the multiprotein complex assembled by FcγRIIb upon its co-clustering with BCR. Gab1 may recruit SH2 domain-containing molecules to the phosphorylated FcγRIIb. SHP-2, activated upon the binding to FcγRIIb-SHIP complex, partially dephosphorylates Gab1, resulting in the release of PtdIns3-K and ultimately in the inhibition of downstream activation pathways in BCR/FcγRIIb co-aggregated cells.

Original languageEnglish
Pages (from-to)3898-3906
Number of pages9
JournalEuropean Journal of Biochemistry
Volume268
Issue number14
DOIs
Publication statusPublished - Sep 29 2001

Keywords

  • B-lymphocytes
  • Fcγ receptors IIb
  • Signal transduction

ASJC Scopus subject areas

  • Biochemistry

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