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

我们研究了STAM的功能意义，STAM先前被鉴定为与细胞因子受体的γ链相关的Jak 3酪氨酸激酶的底物。STAM与Jak 3和Jak 2直接相关，参与IL-2和GM-CSF介导的细胞生长和c-myc诱导的细胞内信号转导，并与TOR介导的信号转导必需分子SLP-76结合。野生型STAM的过表达诱导TCR介导的IL-2启动子活化的增强，表明STAM可能参与TCR介导的信号传导。另一方面，STAM被发现与一种名为AMSH的新分子相互作用。AMSH的功能意义尚未阐明，Grb 2家族的一个新成员Grf 40作为AMSH的相关分子被分离出来，Grf 40还显示与TCR信号传导所必需的SLP-76和LAT结合。Grf 40的SH 2缺失突变体在刺激TCR后抑制IL-2启动子活性的程度显著高于Grb 2的SH 2缺失突变体。这些结果表明Grf 40而不是Grb 2参与了TCR介导的信号传导。总之，本研究中克隆的STAM和Grf 40在TCR介导的信号传导中发挥了重要作用。

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.