| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Antigen-induced ligation of the high affinity IgE receptor (FcεRI) on mast cells triggers a cascade of signaling events that ultimately lead to a wide variety of effector functions: release of granules, production of leukotrienes and prostaglandins, and secretion of cytokines and chemokines. To better understand the regulatory mechanisms of FcεRI-mediated signaling, we examined the role of two protein tyrosine phosphatases (PTPs), PTPε and PTP-PEST, that turned out to be induced upon FcεRI aggregation.
PTPε is a ubiquitously expressed PTP with two PTP domains. There are at least four isoforms generated from one gene : the transmembrane and three cytoplasmic isoforms. We found that bone marrow-derived mast cells from PTPε-deficient mice exhibited enhancement of FcεRI-induced Ca^<2+> mobilization, MAP kinase activation, leading to greater degranulation and cytokine responses. Furthermore, in vivo degranulation induced by IgE and antigen was also elevated in PTPε-deficient mice as assessed by passive systemic anaphylactic reaction. Thus PTPε may serve as a novel negative regulator in FcεRI-mediated mast cell activation (manuscript in preparation).
PTP-PEST, on the other hand, although introduction of substrate-trapping form of PTP-PEST (PTP-PEST-DACS) into RBL-2H3 cells did not affect initial signaling events, it did reduce phosphorylation of phospholipase C-γ and Ca^<2+> mobilization, inhibiting TNF-α expression without affecting degranulation. FcεRI-mediated activation of mitogen-activated protein kinases was also modulated in PTP-PEST-DACS-transfected cells. Significantly, in PTP-PEST-DACS transfectants, phosphoproteins (pp) of 65 kDa and 110 kDa were recruited to PTP-PEST upon FcεRI aggregation. These results suggest that PTP-PEST serve as a novel regulator of distinct aspects of FcεRI-mediated mast cell activation, possibly through actions of pp65 and pp110. We are now in the process of identifying these two phosphoproteins (manuscript in preparation).
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