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Volumn 10, Issue 3, 1998, Pages 306-312

Inhibitory signaling by B cell FcγRIIb

Author keywords

[No Author keywords available]

Indexed keywords

CALCIUM ION; FC RECEPTOR; INOSITOL 1,3,4,5 TETRAKISPHOSPHATE; PHOSPHATASE;

EID: 0344936020     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(98)80169-6     Document Type: Article
Times cited : (126)

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    • of outstanding interest. These experiments addressed the mechanism through which SH2 domain-containing inositol 5-phosphatase (SHIP) was exclusively phosphorylated under negative signaling conditions. Using synthetic phosphopeptides, the authors demonstrated that the SH2 domain of SHIP directly bound the phosphorylated immunoglobulin Fcγ receptor (Fcγ)RIIb immunoreceptor tyrosine-based inhibitory motif (ITIM) motif and related peptides, but not immuno-receptor tyrosine-based activation motif (ITAM)-like sequences. Experiments using FcγRIIb-deficient cell lines revealed that FcγRIIb expression was essential for tyrosine phosphorylation of SHIP and its subsequent interaction with Shc. These findings established a model in which FcγRIIb becomes tyrosine phosphorylated and associates with SHIP prior to, and essential for, SHIP tyrosine phosphorylation.
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    • note
    • 2+ influx was restored to levels seen under positive signaling in B cells lacking SHIP but not SHP-1. In contrast, B cells expressing the killer cell inhibitory receptor required a functional SHP-1 but not SHIP gene product. Together, the data indicated that SHP-1 was not required for B cell negative signaling by immunoglobulin Fcγ receptor (FcγR)IIb and that SHIP was essential. Additional experiments indicated that SHIP-deficient B cells undergo greater activation-induced cell death upon triggering of surface immunoglobulin than normal B cells, suggesting that SHIP protects cellsfrom apoptosis upon its recruitment to FcγRIIb.
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    • of outstanding interest. The authors demonstrated that induction of the Ras pathway, as measured by formation of Ras-GTP or by activity measurements of Raf or Erk (MAP kinase), was greatly reduced under negative signaling conditions. Further studies revealed that the formation of Shc - Grb2 complexes, which is necesary for plasma membrane translocation of Sos, was apparent under positive signaling but not under negative signaling. In contrast, the formation of SH2 domain-containing inositol 5-phosphatase (SHIP) - Shc complexes was greatly enhanced under negative but not positive signaling. The authors proposed that SHIP and Grb2 interact with identical sites on phosphoShc and that the competition between these two proteins under negative signaling conditions can account for reductions in Shc - Grb2 complex formation and the Ras signaling pathway. This model of SH2 domain competition was described in more detail by Tridandapani et al., 1997 [37].
    • Tridandapani S, Chacko GW, Brocklyn JRv, Coggeshall KM. Negative signaling in B cells causes reduced Ras activity by reducing Shc-Grb2 interactions. of outstanding interest J Immunol. 158:1997;1125-1132 The authors demonstrated that induction of the Ras pathway, as measured by formation of Ras-GTP or by activity measurements of Raf or Erk (MAP kinase), was greatly reduced under negative signaling conditions. Further studies revealed that the formation of Shc - Grb2 complexes, which is necesary for plasma membrane translocation of Sos, was apparent under positive signaling but not under negative signaling. In contrast, the formation of SH2 domain-containing inositol 5-phosphatase (SHIP) - Shc complexes was greatly enhanced under negative but not positive signaling. The authors proposed that SHIP and Grb2 interact with identical sites on phosphoShc and that the competition between these two proteins under negative signaling conditions can account for reductions in Shc - Grb2 complex formation and the Ras signaling pathway. This model of SH2 domain competition was described in more detail by Tridandapani et al., 1997 [37].
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    • of special interest. In contrast to the competition model described by Tridandapani et al., 1997 [37,38], these experiments of Xenopus oocyte maturation showed that over-expression of a catalytically inactive but interaction-competent version of SHIP reconstituted the Ras signaling pathway. The authors concluded that SHIP inositol phosphatase activity prevents stimulation of Ras.
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