1. Identification of novel signaling molecules by inducible translocation trap (ITT) Activation of cytokine receptors leads to activation of Jak-family protein tyrosine kinases and Stat transcription factors, and accumulating evidence suggests that Jaks and Stats play important roles in signal transduction from cytokine receptors. On the other hand, our previous research suggests existence of Jak-independent and Stat-independent signal transduction pathways. To identify these elusive signal transduction pathways, we established a novel expression cloning system, inducible translocation trap (ITT), for signaling molecules which translocate into the nucleus upon cytokine stimulation. The basic strategy of this study is based on expression of a fusion protein comprising bacterial LexA DNA-binding domain (LexA DB), transactivation domain of a transcriptional activator, and a test protein. If the test protein translocates into the nucleus upon ligand stimulation, the LexA DB targets the fusion protein to the LexA operator sites of the reporter gene. Then, the transactivation domain activates the reporter expression. By using this novel system, we are attempting to identify novel signaling molecules involved in immune function and development.

2. Functional characterization of novel genes induced by growth-promoting cytokines By using DNA microarray technology, we have identified a novel gene induced by growth promoting cytokines. This gene, cyclon, encodes a nuclear protein with a coiled-coil domain. Functional characterization of cyclon will be performed in the context of lymphocyte proliferation and development.

3. Molecular basis of IL-2R-mediated development of lymphocyte populations Signal transduction from IL-2R subunits is critical for development of natural killer (NK) cells and intraepithelial lymphocytes (IELs). In our previous studies using transgenic mice of IL-2R subunits, we found that transgenic expression of IL-2R subunits affects development of these lymphocytes. We seek to understand molecular mechanisms how development of NK cells and IELs is regulated by signaling form IL-2R subunits.