TRANSDUCTION OF INTERLEUKIN-2 ANTIAPOPTOTIC AND PROLIFERATIVE SIGNALSVIA AKT PROTEIN-KINASE

The interleukin-2 (IL-2) receptor (IL-2R) is composed of three subunit s. Of these, IL-2R alpha is required for high-affinity IL-2 binding, w hile IL-2R beta and IL-2R gamma(c) are required for the transduction o f IL-2-generated signals. Signals transduced via the S region of the I L-2R beta (amino acids 267-322) in BAF/3 cells activate the phosphatid ylinositol 3-kinase (PI3-kinase) and induce the expression of Bcl-2 an d c-myc. Through the induction of Bcl-2, IL-2 inhibits apoptosis and t hrough the combination of Bcl-2 and c-myc it stimulates progression th rough the cell cycle. Here we show that the protein kinase encoded by the Akt proto-oncogene is activated by IL-2. Akt activation by IL-2 de pends on PI3-kinase signals transduced via the S region of the IL-2R b eta and is linked to the translocation of Akt to the cell membrane. Ex pression of catalytically active Akt mutants in BAF/3 cells expressing IL-2R beta[A0]Delta S promotes the expression of Bcl-2 and c-myc, inh ibits apoptosis induced by IL-3 deprivation or staurosporine, and stim ulates cell cycle progression. The same mutants also stimulate cell cy cle progression in 2780a, an IL-2-dependent T cell line that undergoes G(1) arrest rather than apoptosis after IL-2 deprivation. The activat ion of Akt by IL-2 via the PI3-kinase and the rescue of the PI3-kinase -mediated antiapoptotic and proliferative IL-2 signals by catalyticall y active Akt indicate that these signals are transduced by Akt.