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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 15-24
RAPID COMMUNICATION
Identification of a Novel Stat3 Recruitment and Activation Motif Within
the Granulocyte Colony-Stimulating Factor Receptor
Arup Chakraborty,
Kevin F. Dyer,
Michael Cascio,
Timothy A. Mietzner, and
David J. Tweardy
From the Division of Infectious Diseases, the Departments of Medicine
and the Department of Molecular Genetics and Biochemistry, University
of Pittsburgh School of Medicine and the University of Pittsburgh
Cancer Institute, 200 Lothrop St, Pittsburgh, PA.
Stat3 is essential for early embryonic development and for myeloid
differentiation induced by the cytokines granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6). Two isoforms of Stat3 have
been identified,  (p92) and  (p83), which have distinct transcriptional and biological functions. Activation of both Stat3 and Stat3 requires the distal cytoplasmic domain of the G-CSFR, which contains four Tyr at positions 704, 729, 744, and 764. The studies reported here were undertaken to determine which, if any, of
these tyrosine residues participated in Stat3/ recruitment and
activation. We showed that Stat3 and Stat3 were affinity purified
using phosphopeptides containing Y704 and Y744 but not by
nonphosphorylated peptide analogues or by phosphopeptides containing Y729 and Y764. Complementary results were obtained in studies examining
the ability of these peptides to destabilize and inhibit DNA binding of
activated Stat3. Both Y704 and Y744 contributed to optimal activation
of Stat3/ in M1 murine myeloid leukemia cells containing
wild-type and Y-to-F mutant G-CSFR constructs. Carboxy-terminal to Y704
at the +3 position is Gln; YXXQ represents a consensus Stat3
recruitment and activation motif. Y744 is followed at the +3 position
by Cys (C); YXXC, represents a novel motif implicated in the
recruitment and activation of Stat3. Modeling of the SH2 domain of
Stat3 based on homologous SH2 domains of known structure revealed polar
residues whose side chains contact the +3 position. This substitution
may confer specificity for the Y704- and Y744-based ligands by allowing
H-bond formation between the binding surface and the Gln or Cys found
at the respective +3 position.
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