Evidence for two distinct phosphorylation pathways activated by high affinity immunoglobulin E receptors.
The high affinity receptor for immunoglobulin (Ig) E on mast cells, along with the antigen receptors on T and B cells and Fc receptors for IgG, belongs to a class of receptors which lack intrinsic kinase activity, but activate non-receptor tyrosine and serine/threonine kinases. Receptor engagement triggers a chain of signaling events leading from protein phosphorylation to activation of phosphatidylinositol-specific phospholipase C, an increase in intracellular calcium levels, and ultimately the activation of more specialized functions. IgE receptor disengagement leads to reversal of phosphorylation by undefined phosphatases and to inhibition of activation pathways. Here we show that phenylarsine oxide, a chemical which reacts with thiol groups and has been reported to inhibit tyrosine phosphatases, uncouples the IgE receptor-mediated phosphorylation signal from activation of phosphatidyl inositol metabolism, the increase in intracellular calcium levels, and serotonin release. Phenylarsine oxide inhibits neither the kinases (tyrosine and serine/threonine) phosphorylating the receptor and various cellular substrates nor, unexpectedly, the phosphatases responsible for the dephosphorylation following receptor disengagement. By contrast, it abolishes the receptor-mediated phosphorylation of phospholipase C-gamma 1, but not phospholipase C activity in vitro. Therefore the phosphorylation and activation of phospholipase C likely requires a phenylarsine oxide-sensitive element. Receptor aggregation thus activates at least two distinct phosphorylation pathways: a phenylarsine oxide-insensitive pathway leading to phosphorylation/dephosphorylation of the receptor and of various substrates and a sensitive pathway leading to phospholipase C-gamma 1 phosphorylation.
Adamczewski
M
M
Molecular Allergy and Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852.
Paolini
R
R
Kinet
J P
JP
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001152:Arsenicals / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D007073:Immunoglobulin E / Q000378:metabolism*; D007700:Kinetics; D008407:Mast Cells / Q000276:immunology; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D011961:Receptors, Fc / Q000378:metabolism*; D017455:Receptors, IgE; D012701:Serotonin / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D000944:Antigens, Differentiation, B-Lymphocyte; D001152:Arsenicals; D010716:Phosphatidylinositols; D011961:Receptors, Fc; D017455:Receptors, IgE; C029341:oxophenylarsine; D012701:Serotonin; D007073:Immunoglobulin E; D010738:Type C Phospholipases; D002118:Calcium