A novel signal transducing adaptor molecule "STAM" involved in TCR-mediated signal transduction

一种参与TCR介导信号转导的新型信号转导接头分子“STAM”

• 批准号: 09670327
• 负责人: TANAKA Nobuyuki
• 金额: $ 2.24万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670327/
• 关键词: cytokine; TCR; signal transduction; STAM; Grb2 family; tyrosine kinase; T細胞受容体; Crb2ファミリー; IL-2プロモーター

We investigated the functional significance of STAM, which was previously identified as a substrate for the Jak3 tyrosine kinase associated with the gammac chain of the cytokine receptors. STAM was shown to be directly associated with Jak3 and Jak2, and involved in intracellularsignal transduction for cell growth and c-myc induction mediated by at least IL-2 and GM-CSF.Furthermore, STAM was demonstrated to bind to SLP-76, an essential molecule for TOR-mediated signal transduction. Overexpression of the wild-type STAM induced enhancement of IL-2 promoter activation mediated by the TCR, suggesting a possible involvement of STAMin TCR-mediated signaling. On the other hand, STAM was found to interact with a novel molecule named AMSH.Although. the functional significance of AMSH has not yet been clarified, a new member of the Grb2 family, named Grf40, was isolated as an associated molecule with AMSH.Grf40 was also shown to bind to SLP-76 and LAT, which are essential for TCR signaling. The SH2 deletion mutant of Grf40 suppressed IL-2 promoter activity upon stimulation of the TCR significantly more than the SH2 deletion mutant of Grb2. These result suggest that Grf40 rather than Grb2 is involved in signaling mediated by TCR.In conclusion, STAM and Grf40, which were cloned in this research project, were shown to play important roles in the TCR-mediated signaling.

我们研究了STAM的功能意义，STAM先前被确定为与细胞因子受体γ链相关的Jak3酪氨酸激酶的底物。STAM被证明与Jak3和Jak2直接相关，参与细胞内信号转导，至少由IL-2和GM-CSF介导细胞生长和c-myc诱导。此外，STAM被证明与SLP-76结合，SLP-76是tor介导的信号转导的重要分子。野生型STAM过表达诱导TCR介导的IL-2启动子激活增强，提示可能参与了STAMin TCR介导的信号通路。另一方面，STAM被发现与一种名为amsh的新分子相互作用。虽然AMSH的功能意义尚未明确，但Grb2家族的一个新成员Grf40被分离出来作为与AMSH相关的分子。Grf40还被证明与SLP-76和LAT结合，这是TCR信号传导所必需的。Grf40的SH2缺失突变体在TCR刺激下对IL-2启动子活性的抑制显著高于Grb2的SH2缺失突变体。这些结果表明Grf40而不是Grb2参与了TCR介导的信号传导。综上所述，本研究项目克隆的STAM和Grf40在tcr介导的信号通路中发挥重要作用。

项目成果

Asao,H.: "Hrs is associated with STAM, an signal transducing adaptor molecule : Its suppressive effect on cytokine-induced cell growth" J.Biol.Chem.272. 32785-3279 (1997)

Asao,H.：“Hrs 与 STAM（一种信号转导接头分子）相关：其对细胞因子诱导的细胞生长的抑制作用”J.Biol.Chem.272。

Tanaka, N., Abe H., Yagita, H., Okumura, K., Nakamura, M.and Sugamura, K.: "Essential requirement of Itk, a T cell specific tyrosine kinase in CD2-mediated IL-2 promoter activation in human T cell line Jurkat" Eur.J.immunol.27. 834-841 (1997)

Tanaka, N.、Abe H.、Yagita, H.、Okumura, K.、Nakamura, M. 和 Sugamura, K.：“Itk（CD2 介导的 IL-2 启动子激活中的 T 细胞特异性酪氨酸激酶）的基本要求

Oda, K.: "Induction of IL-1 β converting enzyme-independent apoptosis by IL-2 human T cell lines." Int.Immunol.9. 1303-1310 (1997)

Oda, K.：“IL-2 人类 T 细胞系诱导 IL-1 β 转换酶依赖性细胞凋亡。”Int.Immunol.9 (1997)。

田中伸幸: "Induction of IL-1 b converting enzyme-independent apoptosis by IL-2 in human T cell lines." International Journal of Immunology. 9. 1303-1310 (1997)

Nobuyuki Tanaka：“IL-2 在人类 T 细胞系中诱导 IL-1 b 转化酶依赖性细胞凋亡”，《国际免疫学杂志》9. 1303-1310 (1997)。

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.(in press.).

Asada, H.、Ishii, N.、Sasaki, Y.、Endo, K.、Kasai, H.、Tanaka, N.、Takeshita, T.、Tsuchiya, S.、Konno, T. 和 Sugamura, K.：