Grf40, A Novel Grb2 Family Member, Is Involved in T Cell Signaling
Grf40 是 Grb2 家族的新成员,参与 T 细胞信号传导
基本信息
- 批准号:11670310
- 负责人:
- 金额:$ 2.37万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 财政年份:1999
- 资助国家:日本
- 起止时间:1999 至 2000
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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.
我们克隆了一个新的Grb 2家族成员,命名为Grf 40。Grf 40的表达主要在造血细胞,特别是T细胞中。Grf 40比Grb 2更紧密地结合tp SLP-76。顺便提及,Grf 40可能通过其SH 2结构域与用于活化T细胞(LAT)的接头结合。Jurkat细胞中野生型Grf 40的过表达诱导了T细胞受体(TCR)刺激后SLP-76依赖性白细胞介素(IL)-2启动子和活化T细胞核因子(NF-AT)活化的显著增加,而C末端SH 3缺失的Grf 40突变体缺乏IL-2启动子活性的任何可识别的增加。此外,SH 2缺失的Grf 40突变体(Grf 40-dSH 2)导致这些调节活性的显著抑制,其效果明显强于SH 2缺失的Grb 2突变体。我们的数据表明,Grf 40是一个衔接分子参与TCR介导的信号通过一个更有效的相互作用比Grb 2与SLP-76和LAT。为了研究Grf 40的体内功能,我们建立了转基因小鼠表达Grf 40-dSH 2,这是由lck近端启动子驱动。在转基因小鼠中,胸腺细胞总数显著减少,而在双阴性(CD 4-CD 8-)胸腺细胞亚群中,特别是CD 25 + CD 44-前T细胞群显著增加。然而,由前TCR刺激介导的CD 5表达在转基因小鼠的CD 4-CD 8-胸腺细胞上被显著抑制。此外,SLP-76依赖性信号传导也被显著抑制。这些数据表明Grf 40在胸腺细胞中的前TCR以及TCR信号传导中起重要作用。
项目成果
期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Kazuhiro Endo et al.: "STAM2, a new member of the STAM family, binding to the Janus kinases."FEBS Lett.. 477. 55-61 (2000)
Kazuhiro Endo 等人:“STAM2,STAM 家族的新成员,与 Janus 激酶结合。”FEBS Lett.. 477. 55-61 (2000)
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- 影响因子:0
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Kazu Kikuchi et al.: "Suppression of Thymic Development by the Dominant-negative Form of Gads"Int.Immunol.. (in press).
Kazu Kikuchi 等人:“Gads 显性阴性形式对胸腺发育的抑制”Int.Immunol..(出版中)。
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- 影响因子:0
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Hirosi Asada et al.: "Grf40, A Novel Grb2 Family Member, Is Involved in T cell Signaling through Interaction with SLP-76 and LAT"J. Exp. Med.. 189. 1383-1390 (1999)
Hirosi Asada 等人:“Grf40 是一种新的 Grb2 家族成员,通过与 SLP-76 和 LAT 相互作用参与 T 细胞信号传导”J。
- DOI:
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- 影响因子:0
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- 通讯作者:
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. 13
Asada, H.、Ishii, N.、Sasaki, Y.、Endo, K.、Kasai, H.、Tanaka, N.、Takeshita, T.、Tsuchiya, S.、Konno, T. 和 Sugamura, K.:
- DOI:
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- 影响因子:0
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- 通讯作者:
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).
Kikuchi, K.、Kawasaki, Y.、Ishii, N.、Sasaki, Y.、Asao, H.、Takeshita, T.、Miyoshi, I.、Kasai, N.和 Sugamura, K.:“胸腺发育的抑制
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ASAO Hironobu其他文献
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