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RI1
* Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121;
Division of Molecular Cell Immunobiology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan;
National Institute of Vegetable and Tea Science, National Agriculture Research Organization, Shizuoka, Japan; and
Department of Laboratory Medicine, University of California, San Francisco, CA 94143
Aggregation of the high affinity receptor for IgE (Fc
RI) induces activation of mast cells. In this study we show that upon low intensity stimulation of FcRI with monomeric IgE, IgE plus anti-IgE, or IgE plus low Ag, Lyn (a Src family kinase) positively regulates degranulation, cytokine production, and survival, whereas Lyn works as a negative regulator of high intensity stimulation with IgE plus high Ag. Low intensity stimulation suppressed Lyn kinase activity and its association with FcRI 
subunit, whereas high intensity stimulation enhanced Lyn activity and its association with FcRI . The latter induced much higher levels of FcRI phosphorylation and Syk activity than the former. Downstream positive signaling molecules, such as Akt and p38, were positively and negatively regulated by Lyn upon low and high intensity stimulations, respectively. In contrast, the negative regulators, SHIP and Src homology 2 domain-containing protein tyrosine phosphatase-1, interacted with FcRI , and their phosphorylation was controlled by Lyn. Therefore, we conclude that Lyn-mediated positive vs negative regulation depends on the intensity of the stimuli. Studies of mutant FcRI showed that FcRI subunit-ITAM (ITAM motif) regulates degranulation and cytokine production positively and negatively depending on the intensity of FcRI stimulation. Furthermore, Lyn-mediated negative regulation was shown to be exerted via the FcRI -ITAM.
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