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Volume 271, Number 27, Issue of July 5, 1996 pp. 15987-15992
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Persistence of Tyrosine-phosphorylated FcRI in Deactivated Cells

(Received for publication, September 27, 1995, and in revised form, March 26, 1996)

From the Molecular Allergy and Immunology Section, NIAID, National Institutes of Health, Rockville, Maryland 20852

Engagement of the high affinity IgE receptor (FcRI) with a multimeric antigen leads to immediate tyrosine phosphorylation of its  and  subunits, recruitment, and activation of the tyrosine kinase Syk, and later to cell degranulation. Monovalent hapten treatment reverses these events, resulting in receptor dephosphorylation and an abrupt arrest of cell degranulation. Thus far, it has been assumed that there is a direct linkage between receptor tyrosine phosphorylation, Syk activation and phosphorylation, and cell degranulation. However, we show here that when FcRI receptors are cross-linked for extended periods of time, hapten-mediated receptor dephosphorylation is delayed. These receptors, which remain tyrosine-phosphorylated despite the addition of hapten, are progressively targeted to a Triton X-100-insoluble fraction, suggesting their progressive association with the membrane skeleton. In contrast to FcRI receptors, hapten-induced Syk dephosphorylation and the consequent arrest of degranulation are not affected by prolonged cross-linking. Thus, some tyrosine-phosphorylated receptors persist in deactivated cells. We propose that, with time, some tyrosine-phosphorylated receptors become unaccessible to phosphatases and, in addition, unable to activate Syk. This inactive status of tyrosine-phosphorylated FcRI may be the result of membrane skeleton compartmentalization. However, another population of clustered receptors that includes the ones most recently formed is still immediately sensitive to hapten deactivation. This latter population is critical in maintaining Syk activity and cell degranulation. The shift from a transiently active state of phosphorylated receptors toward an inactive state could be a general mechanism of desensitization also utilized by other antigen receptors.

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