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Evidence for a signaling role for the alpha chains of granulocyte-
macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and
IL-5 receptors: divergent signaling pathways between GM-CSF/IL-3 and IL-5
A Mire-Sluis, LA Page, M Wadhwa and R Thorpe
Division of Immunobiology, National Institute for Biological Standards and
Control, Hertsford, UK.
In the present study, we have used a human erythroleukemia cell line, TF-1,
that proliferates in response to granulocyte macrophage colony stimulating
factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) to
investigate the role of receptors for these cytokines in signal
transduction mechanisms involved in proliferative responses. The receptors
for GM-CSF, IL-3, and IL-5 each possess a cytokine specific alpha subunit,
but all three share a common beta chain. Using an immunoblotting system
designed to detect phosphotyrosine containing proteins and a permeabilized
cell system to detect rapid changes in phosphate turnover on proteins, we
show that while GM-CSF and IL-3 use tyrosine phosphorylation to mediate
mitogenic signal transduction, IL-5 uses tyrosine dephosphorylation in its
signaling pathway. The use of different signaling pathways by these
cytokines can be confirmed in a biologic system whereby the proliferation
induced in culture by GM-CSF and IL-3 is inhibited by tyrosine kinase
inhibitors, but that induced by IL-5 is enhanced. Conversely, GM-CSF- and
IL-3-induced proliferation is stimulated by a tyrosine phosphatase
inhibitor, yet IL-5-induced proliferation is inhibited. Inhibitors of
protein kinase C inhibit IL-3- and GM-CSF-, but not IL-5-induced
proliferation. We suggest that, because all these cytokines share the
identical beta chain of their receptors, the cytokine specific alpha chain
mediates the linkage of each receptor to the individual biochemical signal
transduction pathways responsible for the different biologic activities of
these cytokines.
Volume 86,
Issue 7,
pp. 2679-2688,
10/01/1995
Copyright © 1995 by The American Society of Hematology
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