2001 Fiscal Year Final Research Report Summary
Regulation of development of type I allergy by the signal transducer specific for the high-affinity IgE receptor
| Project/Area Number |
11460139
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Basic veterinary science/Basic zootechnical science
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| Research Institution | Tokyo University of Sciences |
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Principal Investigator |
RYO Goitsuka Reseach Institute for Biological Science,Tokyo University of Sciences Associste Professor, 生命科学研究所, 助教授 (50301552)
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| Co-Investigator(Kenkyū-buntansha) |
KATSUHIKO Hayashi Reseach Institute for Biological Science,Tokyo University of Sciences Resarch Associste, 生命科学研究所, 助手 (20287486)
DAISUKE Kitamura Reseach Institute for Biological Science,Tokyo University of Sciences Professor, 生命科学研究所, 教授 (70204914)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Allergy / Signal transduction / IgE receptor / Mast cells |
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| Research Abstract |
MIST is the third member of SLP-76/BASH family signaling proteins, acting downstream of the immunoreceptors. These adaptor proteins are differentially expressed among hematopoietic cells, and very uniquely MIST is only expressed in mast cell lines and cytokine-dependent cell lines. We have demonstrated in this project that MIST is tyrosine phosphorylated upon high-affinity IgE receptor cross linking in mast cells, which is mainly mediated by Lyn kinase. Tyrosine-phosphorylated MIST can inter act with other signaling proteins including PLCy, Vav and Grb 2.The significant reduction of IgE recep-tor-mediated degranulation response was observed when the tyrosine phosphorylation-deficient MIST mutant was expressed in RBL-2H3 rat mast cell line, suggesting that MIST functions as an important scaffold protein for IgE receptor-degranulation. To understand MIST functions in vivo, we generated MIST-deficient mice by gene targeting using ES cell lines. MIST homozygous mice expressed no MIST protein in IL-3-induced bone marrow-derived mast cells and IL-2-induced spleen NK cells. IgE recep tor-mediated degranulation responses as well as cytokine production were profoundly reduced in MIST deficient mast cells, as compared with those in wild-type mast cells. Furthermore, IgE-mediated passive and systemic anaphylaxis in vivo were also attenuated in MIST-deficient mice, indicating that MIST is indeed involved in IgE receptor-mediated mast cell functions in vivo. Based on these findings, we be lieve that MIST would be an excellent target for anti-allergic drugs.
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[Publications] Goitsuka, R., Hayashi, N., Nagase, M., Sasaki, N., Ra, C., Tsujimoto, H., and Hasegawa, A: "Molecular cloning of cDNAs encoding canine highaffinity IgE receptor α, β, and γ-chains."Immunogenestics. 49. 580-58 (1999)
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[Publications] Hayashi, K., Nittono R., Okamoto, N., Kawahara, S., Hara, Y, Goitsuka R., and Kitamura, D: "B cell-restricted adaptor BASH is required for normal development and antigen receptor-mediated activation of B cells."Proc.Natl.Acad.Sci.USA. 97. 2755-2760 (2000)
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[Publications] Goitsuka, R., Kanazashi, H., Sasanuma, H., Fujimura, Y, Hidaka, Y, Tatsuno, A., Ra, C., Hayashi, K., and Kitamura D: "A BASH/SLP-76related adaptor protein MIST/Clnk involved in IgE receptor-mediated degranulation."Int.Imunol. 12. 573-580 (2000)
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[Publications] Fusaki, N., Tomita, S., Wu, Y, Okamoto, N., Goitsuka, R., Kitamura, D., and Hozumi, N: "BLNK is associated with the CD72/SHP-l/Grb2 complex in the WEHI23r cell line after membrane IgM cross-linking."Eur.J.Immunol. 30. 1326-1330 (2000)
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[Publications] Morimura, T., Goitsuka, R., Zhang, Y, Saito, I., Reth, M., and Kitamura, D: "Cell cycle arrest and apoptosis induced by Notchl in B cells."J.Biol.Chem.. 275. 36523-36531 (2000)
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[Publications] Goitsuka, R., Mamada, H., Kitamura, D., Cooper, M. D., and Chen, C-L, H: "Genomic structure and transcriptional regulation of the early B cell gene chB1"J.Immunol. 167. 1454-1460 (2001)
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[Publications] Tsuji, S., Okamoto, M., Yamada, K., Okamoto, N., Goitsuka, R., Arnold, R., Kiefer, F., and Kitamura, D: "DyB cell adaptor containing Src homology 2 domain (BASH) links B cell receptor signaling to the activation of hematopoietic progenitor kinase 1."J.Exp.Med. 194. 529-539 (2001)
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