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Multiple signaling pathways induced by granulocyte colony-stimulating
factor involving activation of JAKs, STAT5, and/or STAT3 are required for
regulation of three distinct classes of immediate early genes
SS Tian, P Tapley, C Sincich, RB Stein, J Rosen and P Lamb
Ligand Pharmaceuticals, San Diego, CA 92121, USA.
Granulocyte colony-stimulating factor (G-CSF) is the major regulator of
proliferation and differentiation of neutrophilic granulocyte precursor
cells. G-CSF activates multiple signaling molecules, including the JAK1 and
JAK2 kinases and the STAT transcription factors. To investigate G- CSF
signaling events regulated by the JAK-STAT pathway, we have generated
UT7-epo cells stably expressing either wild-type (wt) G-CSF receptor or a
series of C-terminal deletion mutants. Gel mobility shift and
immunoprecipitation/Western analysis showed that STAT5 is rapidly activated
by G-CSF in cells expressing the wt G-CSF receptor, in addition to the
previously reported STAT3 and STAT1. Mutants lacking any tyrosine residues
in the cytoplasmic domain maintain their ability to activate STAT5 and
STAT1 but cannot activate STAT3, implying that STAT5 and STAT1 activation
does not require receptor tyrosine phosphorylation. We also observed
significant changes in the ratio of STAT1:STAT3:STAT5 activated by various
G-CSF receptor C-terminal deletion mutants. These mutant receptors were
further used to investigate the role of JAKs and STATs in G-CSF-mediated
responses in these cells. We found that JAK activation correlates with
G-CSF-induced cell proliferation, whereas STAT activation is not required.
We have also identified three classes of G-CSF immediate early genes, whose
activation correlates with the activation of distinct JAK-STAT pathways.
Our data show that, whereas c-fos is regulated through a pathway
independent of STAT activation, oncostatin M, IRF-1, and egr-1 are
regulated by an STAT5-dependent pathway and fibrinogen is regulated by an
STAT3-dependent pathway. In conclusion, our results suggest that G-CSF
regulates its complex biologic activities by selectively activating
distinct early response genes through different JAK-STAT signaling
molecules.
Volume 88,
Issue 12,
pp. 4435-4444,
12/15/1996
Copyright © 1996 by The American Society of Hematology
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