Fcgamma receptor-mediated inhibition of human B cell activation: the role of SHP-2 phosphatase.

Co-clustering of the type II receptors binding the Fc part of IgG (FcgammaRIIb) and B cell receptors results in the translocation of cytosolic, negative regulatory molecules to the phosphorylated immunoreceptor tyrosine-based inhibitory motif (P-ITIM) of the FcgammaRIIb. SH2 domain-containing protein tyrosine phosphatases (SHP-1 and SHP-2), and the polyphosphoinositol 5'-phosphatase (SHIP) ...
have been reported earlier to bind to murine FcgammaRIIb P-ITIM. However, neither the functional substrates of these enzymes, nor the mechanism of the inhibition are fully resolved. We show here that the human FcgammaRIIb binds SHP-2 when co-clustered with the B cell receptors, whereas its synthetic P-ITIM peptide bindes SHP-2 and SHIP in lysates of the Burkitt's lymphoma cell line BL41. The P-ITIM peptide binding enhances SHP-2 activity, resulting in dephosphorylation and release of P-ITIM-bound SHIP and Shc. Moreover, P-ITIM-bound SHP-2 dephosphorylates synthetic peptides corresponding to the sites of tyrosine phosphorylation on SHIP and Shc, indicating that these proteins are its potential substrates. Thus SHP-2-induced dephosphorylation may modulate the intracellular localization and/or activity of SHIP and Shc, thereby inhibiting further activation pathways which they mediate.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Amino Acid Sequence, Animals, B-Lymphocytes, Binding Sites, Cell Line, Humans, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Peptides, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Receptors, IgG, SH2 Domain-Containing Protein Tyrosine Phosphatases, Tyrosine, src-Family Kinases
Eur. J. Immunol.
Date: Jun. 01, 1999
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