Phosphatidylinositol 3-kinase potentiates, but does not trigger, T cell proliferation mediated by the IL-2 receptor

Proliferative signaling by the IL-2R can occur through two distinct pathway s, one mediated by Stat5 and one by the adaptor protein She. Although Stat5 induces T cell proliferation by serving as a transcription factor, the mec hanism of proliferative signaling by She is poorly defined. We examined the roles of two major signaling pathways downstream of She, the p44/p42 mitog en-activated protein kinase (extracellular signal-related kinase (Erk)) and phosphatidylinositol 3-kinase (PI3K) pathways, in promitogenic gene induct ion and proliferation in the IL-2-dependent T cell line CTLL-2. Using IL-2R mutants and specific pharmacologic inhibitors, we found that the PI3K, but not Erk, pathway is required for maximal induction of c-myc, cyclin D2, cy clin D3, cyclin E, and bcl-x(L) by She. To test whether the PI3K pathway is sufficient for proliferative signaling, a tamoxifen-regulated form of PI3K (mp110*ER) was expressed in CTLL-2 cells. Activation of the PI3K pathway t hrough mp110*ER failed p27(Kip1), to up-regulate expression of the c-myc, c yclin D2, cyclin D3, cyclin E, bcl-2, or bcl-X-L genes or down-regulate exp ression of p27 even when coactivated with the Janus kinases (Jak) or the Ra f/Erk pathway. Moreover, mp110*ER induced modest levels of thymidine incorp oration without subsequent cell division. Although insufficient for mitogen esis, mp110*ER enhanced Stat5-mediated proliferative signaling through a me chanism independent of Stat5 transcriptional activity. Thus, in addition to serving a necessary, but insufficient role in Shc-mediated promitogenic ge ne expression, the PI3K pathway contributes to T cell proliferation by pote ntiating mitogenic signaling by Stat5.