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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 1933-1942
Identification of a 14-3-3 Binding Sequence in the Common  Chain of
the Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF),
Interleukin-3 (IL-3), and IL-5 Receptors That Is Serine-Phosphorylated
by GM-CSF
F.C. Stomski,
M. Dottore,
W. Winnall,
M.A. Guthridge,
J. Woodcock,
C.J. Bagley,
D.T. Thomas,
R.K. Andrews,
M.C. Berndt, and
A.F. Lopez
From The Cytokine Receptor Laboratory, The Hanson Centre for Cancer
Research and Institute of Medical and Veterinary Science, Adelaide,
Australia; and the Baker Research Institute, Melbourne, Australia.
The common  chain (c) of the
granulocyte-macrophage colony-stimulating factor (GM-CSF),
interleukin-3 (IL-3), and IL-5 receptors is the major signaling subunit
of these receptors coupling ligand binding to multiple biological
activities. It is thought that these multiple functions arise as a
consequence of the recruitment of specific signaling molecules to
tyrosine-phosphorylated residues in the cytoplasmic domain of
c. However, the contribution of serine phosphorylation
in c to the recruitment of signaling molecules is not
known. We show here the identification of a phosphoserine motif in the
cytoplasmic domain of c that interacts with the adaptor
protein 14-3-3 . Coimmunoprecipitation and pull-down experiments with
a glutathione S-transferase (GST):14-3-3 fusion protein showed that
14-3-3 directly associates with c but not the GM-CSF receptor  chain. C-terminal truncation mutants of c
further showed that a region between amino acids 544 and 626 in
c was required for its association with 14-3-3. This
region contains the sequence 582HSRSLP587,
which closely resembles the RSXSXP (where S is
phosphorylated) consensus 14-3-3 binding site identified in a number of
signaling molecules, including Raf-1. Significantly, substitution of
582HSRSLP587 for EFAAAA completely abolished
interaction of c with GST-14-3-3. Furthermore, the
interaction of c with GST-14-3-3 was greatly reduced in
the presence of a peptide containing the 14-3-3 binding site, but only
when 585Ser was phosphorylated. Direct binding experiments
showed that the peptide containing phosphorylated 585Ser
bound 14-3-3 with an affinity of 150 nmol/L. To study the regulation
of 585S phosphorylation in vivo, we raised antibodies that
specifically recognized 585Ser-phosphorylated
c. Using these antibodies, we showed that GM-CSF
stimulation strongly upregulated 585Ser phosphorylation in
M1 myeloid leukemic cells. The proximity of the SHC-binding site
(577Tyr) to the 14-3-3-binding site
(582HSRSLP587) and their conservation between
mouse, rat, and human c but not in other cytokine
receptors suggest that they form a distinct motif that may subserve
specialized functions associated with the GM-CSF, IL-3, and IL-5 receptors.
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