| Budget Amount *help |
¥17,730,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2007: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2006: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Research Abstract |
Engagement of the high-affinity IgE receptor (FcεRI) on mast cells as well as basophils induces the release of preformed inflammatory mediators by degranulation and also the de novo synthesis and secretion of inflammatory cytokines, leading to an array of acute and chronic allergic symptoms. Two SLP-76 family adaptors, SLP-76 and MIST, are expressed in both mast cells and basophils, and both are involved in FcεRI -signaling. However, the functional redundancy and/or specificity of SLP-76 and MIST in this process remain unclear. In the present study, we intended to clarify the functional redundancy and/or specificity of SLP-76 and MIST in FcεRI-mediated allergic reactions by using mice deficient in MIST and/or SLP-76.
FcεRI-induced degranulation was slightly and profoundly reduced in MIST- and SLP-76-deficient mast cells than in wild type cells, respectively. The residual degranulation detected in SLP-76-deficient cells was completely abrogated by the introduction of a MIST-deficiency. T
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o gain insight into the molecular basis for the functional difference between SLP-76 and MIST in FcεRI-signaling, we examined the mode of molecular interactions and membrane targeting of these two adaptors. SLP-76 associated with Grb2-related adaptor downstream of She (Gads) whereas MIST did not. However, when the Grb2-binding motif in MIST was replaced with a high-affinity RXXK SH3-binding motif from SLP-76, this mutant (MIST-GBF) gained the ability to associate with Gads. Although recruitment and cluster formation of wild type MIST at the antigen contact site were weaker than that observed for SLP-76, the MIST GBF mutant behaved like SLP-76 in terms of these FcεRI-induced changes. Furthermore, expression of MIST-GBF in mast cells enhanced FcεRI-mediated degranulation to a level comparable to that observed in SLP-76-expressing cells, indicating that the presence of the Gads-binding motif (RXXK) determines the functional dominance of SLP-76 over MIST in FcεRI-mediated mast cell activation.
Since SLP-76 is constitutively but MIST is inducibly expressed in mast cells and basophils, these two SLP-76 family adaptors function as a basal essential regulator and an amplifier of FcεRI-mediated mast cell activation, respectively, in allergic reactions. Less
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