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Signal transduction of the human granulocyte-macrophage colony- stimulating
factor and interleukin-3 receptors involves tyrosine phosphorylation of a
common set of cytoplasmic proteins
Y Kanakura, B Druker, SA Cannistra, Y Furukawa, Y Torimoto and JD Griffin
Dana-Farber Cancer Institute, Boston, MA 02115.
Human granulocyte-macrophage colony-stimulating factor (GM-CSF) and
interleukin-3 (IL-3) exert multiple effects on the proliferation,
differentiation, and function of myeloid lineage cells through their
interaction with specific cell-surface receptors. There is a considerable
degree of overlap in the biological effects of these two growth factors,
but little is known about the mechanisms of postreceptor signal
transduction. We have investigated the effects of GM-CSF and IL-3 on
protein tyrosine-kinase activity in a human cell line, MO7E, which
proliferates in response to either factor. Tyrosine- kinase activity was
detected using immunoblotting with a monoclonal antibody (MoAb) specific
for phosphotyrosine. GM-CSF and IL-3 were found to induce a nearly
identical pattern of protein tyrosine phosphorylation using both one- and
two-dimensional gel electrophoresis. Tyrosine phosphorylation of two
cytosolic proteins in particular was increased more than 10-fold, a 93-Kd
protein (pp93) and a 70-Kd protein (pp70). Tyrosine phosphorylation of pp93
and pp70 was observed within 1 minute, reached a maximum at 5 to 15
minutes, and gradually decreased thereafter. Other proteins of 150, 125,
63, 55, 42, and 36 Kd were also phosphorylated on tyrosine in response to
both GM- CSF and IL-3, although to a lesser degree. Tyrosine
phosphorylation was dependent on the concentration of GM-CSF over the range
of 0.1 to 10 ng/mL and on IL-3 over the range of 1 to 30 ng/mL. Stimulation
of MO7E cells with 12-0-tetradecanoyl-phorbol-13-acetate (TPA) or cytokines
such as G-CSF, M-CSF, interleukin-1 (IL-1), interleukin-4 (IL-4),
interleukin-6 (IL-6), interferon gamma, tumor necrosis factor (TNF), or
transforming growth factor-beta (TGF-beta) did not induce tyrosine
phosphorylation of pp93 or pp70, suggesting that these two phosphoproteins
are specific for GM-CSF-or IL-3-induced activation. The extent and duration
of phosphorylation of all the substrates were increased by pretreatment of
cells with vanadate, an inhibitor of protein-tyrosine phosphatases.
Importantly, culture of MO7E cells with vanadate (up to 10 mumol/L)
resulted in a dose-dependent increase in GM- CSF-or IL-3-induced
proliferation of up to 1.8-fold. These results suggest that tyrosine
phosphorylation may be important for GM-CSF and IL-3 receptor-mediated
signal transduction and that cell proliferation may be, at least partially,
regulated by a balance between CSF-induced protein-tyrosine kinase activity
and protein-tyrosine phosphatase activity.
Volume 76,
Issue 4,
pp. 706-715,
08/15/1990
Copyright © 1990 by The American Society of Hematology
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