|Budget Amount *help
¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 1998 : ¥1,500,000 (Direct Cost : ¥1,500,000)
Fiscal Year 1997 : ¥2,000,000 (Direct Cost : ¥2,000,000)
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.