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Activation of phosphatidylinositol-3 kinase by ligation of the
interleukin-7 receptor is dependent on protein tyrosine kinase activity
H Dadi, S Ke and CM Roifman
Division of Immunology/Allergy, University of Toronto, Hospital for Sick
Children, ON.
Ligation of the interleukin-7 receptor (IL-7R) results in a rapid
phosphorylation of tyrosine residues on multiple substrates. In addition,
we have recently shown that the IL-7R mediates activation of
phosphatidylinositol-3 (PI-3) kinase. Because PI-3 kinase activity can be
immunoprecipitated with antiphosphotyrosine antibodies in most receptor
systems studied, it has been examined that either PI-3 kinase or an
associated protein become tyrosine-phosphorylated after ligand binding. We
studied here the possibility that PI-3 kinase, which is directly linked to
mitogenic responses in growth factor receptors, is tyrosine-phosphorylated
after stimulation of the IL-7R. Using anti-p85 alpha or anti-p85 beta
antibodies raised against the p85 subunit of PI- 3 kinase for
immunoprecipitation and subsequent blotting with antiphosphotyrosine
clearly shows that IL-7-stimulated human precursor cells contain both p85
alpha and p85 beta proteins phosphorylated on tyrosine residues. Specific
protein tyrosine kinase inhibitors such as tyrphostin AG-490 block total
cell lysate phosphorylation and tyrosine phosphorylation on p85. Similar
concentrations of this inhibitor also block in vitro and in vivo PI-3
kinase activity suggesting that this enzyme activation is dependent on the
phosphorylation event of p85. In addition, AG-490 blocks IL-7-mediated
proliferation in a dose-dependent manner, suggesting a link between the
early events of PI-3 kinase phosphorylation and activation with
IL-7R-induced cell growth.
Volume 84,
Issue 5,
pp. 1579-1586,
09/01/1994
Copyright © 1994 by The American Society of Hematology
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