Abstract
Hemopoietic cells respond to cytokines by initiating tyrosine phosphorylation of receptors and receptor-associated proteins, leading to the activation of numerous cytosolic and membrane associated enzymes, including phosphatidylinositol 3-OH kinase (PI 3-kinase). Recent reports have suggested that PI 3-kinase may serve as an upstream activator of mitogen-activated protein (MAP) kinase. After stimulation with interleukin-3 and granulocyte-macrophage colony-stimulating factor, we show here that inhibition of MAP kinase activity by two inhibitors of PI 3-kinase, wortmannin and LY-294002, does not correlate with their ability to inhibit PI 3-kinase or p70 S6 kinase phosphorylation. Complete inhibition of phosphatidylinositol 3,4,5-trisphosphate production occurred at approximately 100 nM WM or 25 microM LY-294002, but at these concentrations, WM significantly inhibited MAP kinase activation, while LY-294002 had virtually no effect on MAP kinase activity. Furthermore, WM does not inhibit phorbol ester-mediated MAP kinase activation, but LY-294002 does. Together these results suggest WM and LY-294002 are differentially inhibiting enzymes other than PI 3-kinase that function upstream of MAP kinase.
Highlights
Since the IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors share a common  subunit, and many studies have shown that they stimulate the same signal transduction pathways, it will be interesting to determine how GM-CSF is able to bypass the effects of the PI 3-kinase inhibitors
We have continued our investigation of the signaling network downstream of IL-3 and GM-CSF receptors to examine the role of the p21ras and mitogen-activated protein (MAP) kinase pathways in inhibition of apoptosis
Consistent with our previous studies, we show that the activation of MAP kinase by either IL-3 or GM-CSF is kinase
Summary
We examined the effects of WM on MAP kinase activity in MC-9 cells stimulated with either IL-3 or GM-CSF These results show the GM-CSF-stimulated MAP kinase activity from cells treated with various doses of either WM or LY-294002.
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