Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FeγRIIB

Abstract

Immune complexes are potent activators of inflammatory cells, triggering effector responses through the crosslinking of Fc receptors (FcRs) such as Fc(epsilon)RI or Fc(gamma)RIII. On B cells and mast cells, immune complexes are also negative regulators of activation triggered by antigen and Fc receptors, a consequence of coligation of the B-cell antigen receptor or Fc(epsilon)RI, respectively, and the inhibitory receptor Fc(gamma)RIIB. Here we show that inhibitory signalling by Fc(gamma)RIIB does not require the SH2-domain-containing protein tyrosine phosphatase, SHP-1, in mast cells and results in the recruitment of the SH2-domain-containing inositol polyphosphate 5-phosphatase, SHIP, to the tyrosine-phosphorylated 13-amino-acid inhibitory motif of Fc(gamma)RIIB in both B cells and mast cells. SHIP, by hydrolysing the 5-phosphate of phosphatidylinositol(3,4,5)P3 and inositol(1,3,4,5)P4, suggests a mechanism by which Fc(gamma)RIIB can inhibit calcium influx and downstream responses triggered by immune receptors.

Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF Receptor 3 signaling

“…After Western blot, proteins were revealed with anti SOS (which recognizes both SOS1 and 2), anti myc and anti FLT4 antibodies FLT4L interferes only with the formation of FLT4L-SHC complex whereas overexpression of SHC PTB protein probably competes the binding of SHC with FLT4L but also with other proteins. For example, a likely target of SHC PTB domain is SHIP, a phosphatidylinositol phosphatase that inhibits the signaling mediated by Insulin and immune receptors like FcgRIIB (Lioubin et al, 1996;Ono et al, 1996;Deuter-Reinhard et al, 1997). The expression of SHC PTB construct may disrupt the pool of SHIP-SHC complex and interfere with the inhibitory signaling of SHIP.…”

BCR – ABL accelerates C2-ceramide-induced apoptosis

“…Of note, the protein-speci®c immunoprecipitation studies indicated that BCR ± ABL was present in the anti-Cbl immunoprecipitates (Figure 8c), consistent with the possibility that ceramide activates BCR ± ABL which then phosphorylates tyrosine residues on Cbl. The speci®c immunoprecipitation studies also revealed that short term exposure of BCR ± ABL + BAF3 cells, but not NEO ± BAF3 cells to C2-ceramide induced an association of Shc with a tyrosine phosphorylated form of SHIP (Figure 8b), an SH2-containing 5-phosphatase Lioubin et al, 1996) recently implicated in mediating apoptosis and negative signaling (Liu et al, 1997;Lioubin et al, 1996;Chacko et al, 1996;Ono et al, 1996). …”

Chimeric Human Fcγ–Allergen Fusion Proteins in the Prevention of Allergy

“…Human mast cells and basophils express FcγRIIb, which contains an immunoreceptor tyrosine-based inhibitory motif (ITIMs) within its cytoplasmic tail (9). Co-aggregation of FcεRI to FcγRIIb has been shown to block in vitro and in vivo human basophil and mast cell function (10)(11)(12)(13). This inhibition is mediated via the reduction in the tyrosine phosphorylation of Syk, ERK and several other cellular substrates and increased tyrosine phosphorylation of the adapter protein downstream of kinase (Dok) growth factor receptor-bound protein 2 (Grb2) and SH2 domain containing inositol 5-phosphatase (SHIP) (8,14).…”