2000 Fiscal Year Final Research Report Summary
Grf40, A Novel Grb2 Family Member, Is Involved in T Cell Signaling
| Project/Area Number |
11670310
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | Tohoku University |
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Principal Investigator |
ASAO Hironobu Graduate School of Medicine, Tohoku University, Associate Professor, 大学院・医学系研究科, 助教授 (80250744)
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Naoto Graduate School of Medicine, Tohoku University, Research Associate, 大学院・医学系研究科, 助手 (60291267)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Grf40 / Gads / TCR / Grb2 family / signal transduction |
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| Research Abstract |
We molecularly cloned a new Grb2 family member, named Grf40. Expression of Grf40 is predominant in hematopoietic cells, particularly T cells. Grf40 binds tp SLP-76 more tightly than Grb2. Incidentally, Grf40 binds to linker for activation of T cells (LAT) possibly via its SH2 domain. Overexpression of wild-type Grf40 in Jurkat cells induced a significant increase of SLP-76-dependent interleukin (IL)-2 promoter and nuclear factor of activated T cell (NF-AT) activation upon T cell receptor (TCR) stimulation, whereas the C-terminal SH3-deleted Grf40 mutant lacked any recognizable increase in IL-2 promoter activity. Furthermore, the SH2-deleted Grf40 mutant (Grf40-dSH2) led to a marked inhibition of these regulatory activities, the effect of which is apparently stronger than that of the SH2-deleted Grb2 mutant. Our data suggest that Grf40 is an adaptor molecule involved in TCR-mediated signaling through a more efficient interaction than Grb2 with SLP-76 and LAT.To investigate an in vivo function of Grf40, We generated transgenic mice expressing Grf40-dSH2, which is driven by the lck proximal promoter. The total number of thymocytes was profoundly reduced in the transgenic mice, whereas in the double-negative (CD4-CD8-) thymocyte subset, in particular, the CD25+CD44-pre-T cell population was significantly increased. However, CD5 expression, which is mediated by pre-TCR stimulation, was significantly suppressed on the CD4-CD8-thymocytes of the transgenic mice. Furthermore, the SLP-76-dependent signaling was markedly suppressed as well. These data suggest that Grf40 plays an important role in the pre-TCR as well as TCR signaling in thymocytes.
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[Publications] Asada, H., Ishii, N., Sasaki, Y., Endo, K., Kasai, H., Tanaka, N., Takeshita, T., Tsuchiya, S., Konno, T.and Sugamura, K.: "Grf40, A Novel Grb2 Family Member, Is Involved in T Cell Signaling through Interaction with SLP-76 and LAT."J.Exp.Med.. Vol.189. 1383-1390 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Kikuchi, K., Kawasaki, Y., Ishii, N., Sasaki, Y., Asao, H., Takeshita, T., Miyoshi, I., Kasai, N.and Sugamura, K.: "Suppression of Thymic Development by the Dominant-negative Form of Gads."Int.Immunol.. (in press).
Description
「研究成果報告書概要(欧文)」より
