FC-GAMMA-RI COUPLING TO PHOSPHOLIPASE-D INITIATES SPHINGOSINE KINASE-MEDIATED CALCIUM MOBILIZATION AND VESICULAR TRAFFICKING

Aggregation of receptors specific for the constant region of immunoglo bulin G activates a repertoire of monocyte responses that can lead ult imately to targeted cell killing via antibody-directed cellular cytoto xicity. The high affinity receptor, Fc gamma RI, contains no recognize d signaling motif in its cytoplasmic tail but rather utilizes the gamm a-chain of Fc epsilon RI as an accessory molecule to recruit tyrosine kinases for signal transduction. We show here that, in a human monocyt ic cell line primed with interferon-gamma, Fc gamma RI mobilizes intra cellular calcium stores using a novel pathway that involves tyrosine k inase coupling to phospholipase D and resultant downstream activation of sphingosine kinase, Moreover, Fc gamma RI is not coupled to phospho lipase C; hence, calcium release from intracellular stores occurred in the absence of any measurable rise in inositol triphosphate. Finally, as this novel activation pathway is also shown to be responsible for mediating the vesicular trafficking of internalized immune complexes f or degradation, it is likely to play a key role in controlling intrace llular events triggered by Fc gamma RI.