Fcγ 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 (FcγRIIb) 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 FcγRIIb. 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 FcγRIIb 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 FcγRIIb 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.