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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 867-876
Characterization of the Role of the Human Granulocyte-Macrophage
Colony-Stimulating Factor Receptor  Subunit in the Activation of
JAK2 and STAT5
Sean E. Doyle and
Judith C. Gasson
From the Molecular Biology Institute, UCLA, Los Angeles; and the
Division of Hematology-Oncology, Department of Medicine, Department of
Biological Chemistry, and Jonsson Comprehensive Cancer Center, UCLA
School of Medicine, Los Angeles, CA.
The high-affinity human granulocyte-macrophage colony-stimulating
factor (GM-CSF) receptor (GMR) consists of an alpha (GMR ) and a
common beta ( c) subunit. The intracellular domain of c has been
extensively characterized and has been shown to be critical for the
activation of both the JAK/STAT and MAP kinase pathways. The function
of the intracellular domain of GMR, however, is not as well
characterized. To determine the role of this domain in GMR signaling,
an extensive structure-function analysis was performed. Truncation
mutants 362, 371, and 375 were generated, as well as the
site-directed mutants VQVQ and VVVV. Although 375,
VQNQ, and VVVV stimulated proliferation in response to
human GM-CSF, the truncation mutants 362 and 371 were
incapable of transducing a proliferative signal. In addition, both
371 and VVVV were expressed at markedly reduced levels,
indicating the importance of residues 372 to 374 for proper protein
expression. More importantly, we show that GMR plays a direct role
in the activation of the JAK/STAT pathway, and electrophoretic mobility shift assays (EMSA) indicate that both GMR and c play a role in
determining the STAT5 DNA binding complex activated by the GMR. Thus,
the intracellular domain of the human GMR is important for
activation of the JAK/STAT pathway and protein stabilization.
© 1998 by The American Society of Hematology.
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