A molecular switch changes the signalling pathway used by the Fc gamma RI antibody receptor to mobilise calcium.
BACKGROUND
Leukocytes express Fc gamma receptors, which are specific for the constant region of immunoglobulin G. Aggregation of these receptors activates a repertoire of responses that can lead to targeted cell killing by antibody-directed cellular cytotoxicity. The nature of the myeloid response to Fc gamma receptor aggregation is highly variable and depends on the maturation state of the cell, but little is known about the signalling mechanisms underlying this variability.


RESULTS
We show here that differentiation of a monocytic cell line, U937, to a more macrophage phenotype resulted in an absolute and fundamental switch in the nature of the phospholipid signalling pathway recruited following Fc gamma receptor aggregation. In cytokine-primed monocytes, aggregation of the high-affinity receptor Fc gamma RI resulted in the activation of phospholipase D and sphingosine kinase, which in turn led to the transient release of stored calcium; these effects were mediated by the gamma chain, an Fc gamma RI accessory protein. In contrast, in cells differentiated to a more macrophage type, aggregation of Fc gamma RI resulted in the Fc gamma RIIa-mediated activation of phospholipase C, and the resulting calcium response was prolonged as calcium entry was stimulated.


CONCLUSIONS
The switch in Fc gamma RI signalling pathways upon monocyte differentiation is mediated by a switch in the accessory molecule recruited by Fc gamma RI, which lacks its own intrinsic signal transduction motif. As many immune receptors have separate polypeptide chains for ligand binding and signal transduction (allowing a similar switch in signalling pathways), the mechanism described here is likely to be widely used.
Melendez
A
A
Department of Medicine & Therapeutics, University of Glasgow, Scotland, UK.
Floto
R A
RA
Cameron
A J
AJ
Gillooly
D J
DJ
Harnett
M M
MM
Allen
J M
JM
D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004075:Diglycerides / Q000096:biosynthesis; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D010739:Phospholipase D / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099157:Sphingosine Kinase
D003994:Bucladesine; D002118:Calcium; D004075:Diglycerides; D007371:Interferon-gamma; D010739:Phospholipase D; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D017452:Receptors, IgG; D000099157:Sphingosine Kinase