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Mol Cell Biol, February 1998, p. 742-752, Vol. 18, No. 2
Department of Molecular and Developmental
Biology1 and
Department of Stem Cell
Regulation,2 The Institute of Medical Science,
The University of Tokyo, Minato-ku, Tokyo 108, Japan
Received 15 May 1997/Accepted 30 October 1997
Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces
various functions, including the proliferation and differentiation of a
broad range of hematopoietic cells. We previously reported that at
least two distinct pathways are involved in human GM-CSF receptor
signaling; both require the box 1 region of the common
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Copyright © 1998, American Society for Microbiology. All rights reserved.
Definition of the Role of Tyrosine Residues of the
Common
Subunit Regulating Multiple Signaling Pathways of
Granulocyte-Macrophage Colony-Stimulating Factor Receptor
subunit
(
c). This region is essential for the activation of JAK2, which is
necessary for all the biological functions of GM-CSF. The activation of
JAK2 by GM-CSF leads to rapid tyrosine phosphorylation of cellular
proteins, including the
c. However, the significance of
c
phosphorylation with regard to the regulation of signaling molecules
and the expression of GM-CSF functions is less well understood. Here we
investigated the role of the cytoplasmic tyrosine residues of the
c
by using a series of
c mutants expressed in murine BA/F3 cells. A
mutant
c with all eight cytoplasmic tyrosines converted to
phenylalanine (Fall) activated JAK2 but not SHP-2, MAPK cascades,
STAT5, or the c-fos promoter in BA/F3 cells, and it did not
effectively induce proliferation. Adding back each tyrosine to Fall
revealed that Tyr577, Tyr612, and Tyr695 are involved in the activation
of SHP-2, MAPK cascades, and c-fos transcription, while
every tyrosine, particularly Tyr612, Tyr695, Tyr750, and Tyr806,
facilitated STAT5 activation. Impaired growth was also restored, at
least partly, by any of the tyrosines. These results provide evidence
that
c tyrosines possess distinct yet overlapping functions in
activating multiple signaling pathways induced by GM-CSF.
*
Corresponding author. Mailing address: Department of
Molecular and Developmental Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108, Japan. Phone: 81-3-5449-5660. Fax: 81-3-5449-5424. E-mail: sumiko{at}ims.u-tokyo.ac.jp.
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