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Mol. Cell. Biol., 06 1995, 3049-3057, Vol 15, No. 6
Copyright © 1995, American Society for Microbiology

Interleukin-2 triggers a novel phosphatidylinositol 3-kinase-dependent MEK activation pathway

LM Karnitz, LA Burns, SL Sutor, J Blenis and RT Abraham
Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

Phosphatidylinositol 3-kinase (PI3-K) has been implicated as a signal- transducing component in interleukin-2 (IL-2)-induced mitogenesis. However, the function of this lipid kinase in regulating IL-2-triggered downstream events has remained obscure. Using the potent and specific PI3-K inhibitor, wortmannin, we assessed the role of PI3-K in IL-2- mediated signaling and proliferation in the murine T-cell line CTLL-2. Addition of the drug to exponentially growing cells resulted in an accumulation of cells in the G0/G1 phase of the cell cycle. Furthermore, wortmannin also partially suppressed IL-2-induced S-phase entry in G1-synchronized cells. Analysis of IL-2-triggered signaling pathways revealed that wortmannin pretreatment resulted in complete inhibition of IL-2-provoked p70 S6 kinase activation and also attenuated IL-2-induced MAP kinase activation at drug concentrations identical to those required for inhibition of PI3-K catalytic activity. Wortmannin also diminished the IL-2-triggered activation of the MAP kinase activator, MEK, but did not inhibit activation of Raf, the canonical upstream activator of MEK. These results suggest that a novel wortmannin-sensitive activation pathway regulates MEK and MAP kinase in IL-2-stimulated T lymphocytes.


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