Deletion of the acidic-rich domain of the IL-2Rβ chain increases receptor-associated PI3K activity

AbstractInterleukin-2 (IL-2) regulates the proliferation and homeostasis of lymphocytes through the coordinated activation of distinct signaling pathways. Deletion of the acidic-rich domain of the IL-2 receptor β chain (IL-2Rβ) prevents association of Src tyrosine kinases to the receptor, as well as IL-2-induced Akt activation. Cells bearing this deletion (BafβΔA) maintain full proliferation in response to IL-2 both in vivo and in vitro, suggesting that those pathways are dispensable for this important function of IL-2. In this study, we re-examined phosphatidylinositol-3 kinase (PI3K) activation in BafβΔA cells and found that, in BaF/3 IL-2RβΔA cells, deletion of the acidic domain induced constitutive activation of the receptor-associated PI3K activity. This, in turn, was responsible for the higher basal Akt activity observed in cells expressing this deletion. Based on these data, and since pharmacological abrogation of PI3K activity prevented IL-2-driven cell proliferation of BafβΔA cells, we conclude that the PI3K/Akt pathway is still functionally relevant in cells bearing this mutation. Moreover, we show that the PI3K-induced signals are, at least in part, responsible for c-myc expression. In conclusion, we have used this model to better identify those signals that are integral components of the molecular mechanisms responsible for IL-2-regulated cell proliferation