Anti-apoptotic signaling by the interleukin-2 receptor reveals a function for cytoplasmic tyrosine residues within the common γ (γc) receptor subunit

Abstract

The interleukin-2 receptor (IL-2R) is composed of one affinity-modulating subunit (IL-2Rα) and two essential signaling subunits (IL-2Rβ and γc). Although most known signaling events are mediated through tyrosine residues located within IL-2Rβ, no functions have yet been ascribed to γc tyrosine residues. In this study, we describe a role for γc tyrosines in anti-apoptotic signal transduction. We have shown previously that a tyrosine-deficient IL-2Rβ chain paired with wild type γc stimulated enhancement of bcl-2 mRNA in IL-2-dependent T cells, but it was not determined which region of the IL-2R or which pathway was activated to direct this signaling response. Here we show that up-regulation of Bcl-2 by an IL-2R lacking IL-2Rβ tyrosine residues leads to increased cell survival after cytokine deprivation; strikingly, this survival signal does not occur in the absence of γc tyrosine residues. These γc-dependent signals are revealed only in the absence of IL-2Rβ tyrosines, indicating that the IL-2R engages at least two distinct signaling pathways to regulate apoptosis and Bcl-2 expression. Mechanistically, the γc-dependent signal requires activation of Janus kinases 1 and 3 and is sensitive to wortmannin, implicating phosphatidylinositol -kinase. Consistent with involvement of phosphatidylinositol 3-kinase, Akt can be activated via tyrosine residues on γc. Thus, γc mediates an anti-apoptotic signaling pathway through Akt which cooperates with signals from its partner chain, IL-2Rβ.