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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 113-124
Tyrosine-Dependent and -Independent Mechanisms of STAT3
Activation by the Human Granulocyte Colony-Stimulating Factor
(G-CSF) Receptor Are Differentially Utilized Depending on G-CSF
Concentration
Alister C. Ward,
Mirjam H.A. Hermans,
Louise Smith,
Yvette M. van
Aesch,
Anita M. Schelen,
Claudia Antonissen, and
Ivo P. Touw
From the Institute of Hematology, Erasmus University, Rotterdam; and
the Department of Hematology, Dr Daniel den Hoed Cancer Center,
Rotterdam, The Netherlands.
The granulocyte colony-stimulating factor receptor
(G-CSF-R) activates multiple STAT proteins. Although the
membrane-proximal cytoplasmic region of the G-CSF-R is necessary and
sufficient for activation of STAT1 and STAT5, activation of STAT3
requires the membrane distal region that contains four tyrosines.
Although one of these (Y704) has previously been shown to be involved
in STAT3 activation from a truncated G-CSF-R derived from a patient with severe chronic neutropenia (SCN), this tyrosine is not required for STAT3 activation by the full-length G-CSF-R. To investigate possible alternative mechanisms of STAT3 activation, we generated a
series of Ba/F3 cell transfectants expressing the wild-type G-CSF-R or
mutant receptors that either completely lack tyrosines or retain just
one of the four cytoplasmic tyrosines of the G-CSF-R. We show that, at
saturating G-CSF concentrations, STAT3 activation from the full-length
G-CSF-R is efficiently mediated by the C-terminal domain in a manner
independent of receptor tyrosines. In contrast, at low G-CSF
concentrations, Y704 and Y744 of the G-CSF-R play a major role in STAT3
activation. Both tyrosine-dependent and -independent mechanisms of
STAT3 activation are sensitive to the Jak2 inhibitor AG-490, follow
similar kinetics, and lead to transactivation of a STAT3 reporter
construct, indicating functional equivalence. STAT3 activation is also
impaired, particularly at nonsaturating G-CSF concentrations, in bone
marrow cells from mice expressing a truncated G-CSF-R
(gcsfr- 715). These findings suggest that G-CSF-induced STAT3 activation during basal granulopoiesis (low G-CSF)
and "emergency" granulopoiesis (high G-CSF) are differentially controlled. In addition, the data establish the importance of the
G-CSF-R C-terminus in STAT3 activation in primary cells, which has
implications for understanding why truncated G-CSF-R derived from SCN
patients are defective in maturation signaling.
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