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. 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.
Karnitz
L M
LM
Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Burns
L A
LA
Sutor
S L
SL
Blenis
J
J
Abraham
R T
RT
D000730:Androstadienes / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D007376:Interleukin-2; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D020929:Mitogen-Activated Protein Kinase Kinases; D000077191:Wortmannin