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Erythropoietin induces tyrosine phosphorylation of the interleukin-3
receptor beta subunit (betaIL3) and recruitment of Stat5 to possible
Stat5-docking sites in betaIL3
H Chin, H Wakao, A Miyajima, R Kamiyama, N Miyasaka and O Miura
First Department of Internal Medicine and School of Allied Health Sciences,
Tokyo Medical and Dental University, Bunkyoku, Japan.
The receptors for erythropoietin (Epo) and interleukin-3 (IL-3) both induce
the ligand-dependent activation of the Jak2 tyrosine kinase. Activated Jak2
then phosphorylates these receptors and thereby recruits various signaling
molecules containing the Src homology (SH)-2 domain, including Stat5, to
the tyrosine phosphorylated receptors. In the present study, we demonstrate
that Epo stimulation induces unidirectional cross-phosphorylation of the
IL-3 receptor beta subunit (betaIL3) on tyrosines and its rapid and
transient association with Stat5 in murine IL-3-dependent cell lines
engineered to express the Epo receptor (EpoR). Using cell lines expressing
various EpoR mutants, it was demonstrated that the Epo-induced tyrosine
phosphorylation of betaIL3 is dependent on the membrane-proximal EpoR
cytoplasmic region involved in the activation of Jak2, but not on the
extracellular and transmembrane regions or on the carboxy-terminal 145
amino acid region containing all the intracellular tyrosine residues. It
was also shown that IL-3 induces rapid and dose-dependent association of
Jak2 with betaIL3. However, Epo failed to induce any detectable association
of betaIL3 with Jak2 or the EpoR. The present study also demonstrates that
in IL-3-stimulated cells, an ovine Stat5 mutant harboring a substitution of
Tyr694 to Phe, which abolishes the tyrosine phosphorylation required for
activation, fails to dimerize with endogenous Stat5, shows sustained
binding with tyrosine-phosphorylated betaIL3, and inhibits the tyrosine
phosphorylation of endogenous Stat5. These results suggest that betaIL3 may
have Stat5 docking sites, similar to those found in the EpoR, that
facilitate the activation of Stat5 by Jak2 and raise the possibility that
Epo may cross-activate or transmodulate the IL-3 receptor signaling
pathways.
Volume 89,
Issue 12,
pp. 4327-4336,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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