INTERLEUKIN-2 TRIGGERS A NOVEL PHOSPHATIDYLINOSITOL 3-KINASE-DEPENDENT MEK ACTIVATION PATHWAY

Phosphatidylinositol 3-kinase (PI3-K) has been implicated as a signal- transducing component in interleukin-2 (IL-2)-induced mitogenesis. How ever, the function of this lipid kinase in regulating IL-2-triggered d ownstream events has remained obscure. Using the potent and specific P I3-K inhibitor, wortmannin, we assessed the role of PI3-K in IL-2-medi ated signaling and proliferation in the murine T-cell line CTLL-2. Add ition of the drug to exponentially growing cells resulted in an accumu lation of cells in the G(0)/G(1) phase of the cell cycle. Furthermore, wortmannin also partially suppressed IL-2-induced S-phase entry in G( 1)-synchronized cells. Analysis of IL-2-triggered signaling pathways r evealed that wortmannin pretreatment resulted in complete inhibition o f IL-2-provoked p70 S6 kinase activation and also attenuated IL-2-indu ced MAP kinase activation at drug concentrations identical to those re quired for inhibition of PI3-K catalytic activity. Wortmannin also dim inished the IL-2-triggered activation of the MAP kinase activator, MEK , but did not inhibit activation of Rat, the canonical upstream activa tor of MEK. These results suggest that a novel wortmannin-sensitive ac tivation pathway regulates MEK and MAP kinase in IL-2-stimulated T lym phocytes.