Analysis of intracellular signal transduction mediated by the cytokine receptor

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Interleukin (IL-2) plays a crrucial role in regulating proliferation of activated T cells. IL-2 exerts its biological activities through the binding to its specific receptor (IL-2R) on target cells, although it remained elusive how the functional high-affinity IL-2R (consisting of alpha, beta, and gamma chains) transduce IL-2 signals to cell interior. Previous studies demonstrate that the cytyoplasmic regions of both the IL-2Rbeta and gamma chains play important roles in IL-2-induced proliferative signal transmission, and that the cytoplasmic region of the beta chain couples physically and functionally with the Src-family protein tyrosine kinases (PTKs), Lck and Fyn. In this study we found that the sytoplasmic regions of beta and gamma chains also couple both physically and functionally with a series of non-receptor PTKs, Syk, a member of the Syk/ZAP-70-family PTKs, and Jak1 and Jak3, members of the Jak-family PTKs. In addition, we identified a novel protein serine/threonine kinase(s) that associates physically with the cytoplasmic region of the beta chain, although its functional role in IL-2 signaling is still unclear. Furthermore, it was found that protein tyrosine phosphatase, SHP-2, that possesses an SH2 region, is tyrpsine phosphorylated upon IL-2 stimulation. In this study we also identified target genes of IL-2 signals ; i.e.bcl-2 proto-oncogene, a gene encoding the protein tyrosine phosphatase LC-PTP,and BAG-1 gene. Structure-function analyzes of the beta chain revealed that induction of both bcl-2 and BAG-1 genes requires the cytoplasmic "serine-rich" region of the beta chain. On the other hand, the induction of LC-PTP gene requies both the cytoplasmic "serine-rich" and "acidic" regions of the beta chain. We also obtained the results suggesting potential role of Bcl-2 in IL-2-induced cell cycle progression.