The SH2-containing 5'-inositol phosphatase (SHIP) is tyrosine phosphorylated after Fc gamma receptor clustering in monocytes.
Current models of Fc gamma R signal transduction in monocytes describe a molecular cascade that begins upon clustering of Fc gamma R with the phosphorylation of critical tyrosine residues in the cytoplasmic domains of Fc gamma RIIa or the gamma-chain subunit of Fc gamma RI and Fc gamma RIIIa. The cascade engages several other tyrosine-phosphorylated molecules, either enzymes or adapters, to manifest ultimately an array of biological responses, including phagocytosis, cell killing, secretion of a variety of inflammatory mediators, and activation. Continuing to assess systematically the molecules participating in the cascade, we have found that the SH2-containing 5'-inositol phosphatase (SHIP) is phosphorylated on tyrosine early and transiently after Fc gamma R clustering. This molecule in other systems, such as B cells and mast cells, mediates an inhibitory signal. We find that clustering of either Fc gamma RIIa or Fc gamma RI is effective in inducing SHIP phosphorylation, that SHIP binds in vitro to a phosphorylated immunoreceptor tyrosine-based activation motif, peptide from the cytoplasmic domain of Fc gamma RIIa in activation-independent fashion, although SHIP binding increases upon cell activation, and that Fc gamma RIIb and Fc gamma RIIc are not responsible for the observed SHIP phosphorylation. These findings prompt us to propose that SHIP inhibits Fc gamma R-mediated signal transduction by engaging immunoreceptor tyrosine-based activation motif-containing cytoplasmic domains of Fc gamma RIIa and Fc gamma RI-associated gamma-chain.
Maresco
D L
DL
Department of Internal Medicine, Ohio State University, Columbus 43210, USA.
Osborne
J M
JM
Cooney
D
D
Coggeshall
K M
KM
Anderson
C L
CL
D004800:Enzymes, Immobilized; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007164:Immunosorbents / Q000378:metabolism; D007700:Kinetics; D046911:Macromolecular Substances; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000302:isolation & purification / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D020298:U937 Cells; D018909:src Homology Domains / Q000276:immunology*
D004800:Enzymes, Immobilized; D007140:Immunoglobulin Fab Fragments; D007164:Immunosorbents; D046911:Macromolecular Substances; D010455:Peptides; D010750:Phosphoproteins; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D019000:Phosphotyrosine; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases