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Physical and functional interactions between Stat5 and the tyrosine-
phosphorylated receptors for erythropoietin and interleukin-3
H Chin, N Nakamura, R Kamiyama, N Miyasaka, JN Ihle and O Miura
First Department of Internal Medicine and School of Allied Health Sciences,
Tokyo Medical and Dental University, Japan.
Erythropoietin (Epo) and interleukin-3 (IL-3) stimulate activation of the
Jak2 tyrosine kinase and induce tyrosine phosphorylation and activation of
Stat5. In the present study, we have shown that Epo or IL- 3 stimulation
induces binding of Stat5 to the tyrosine-phosphorylated Epo receptor (EpoR)
or IL-3 receptor beta subunit (betaIL3), respectively, in IL-3-dependent
32D cells expressing the EpoR. The binding of Stat5 to these cytokine
receptors was shown to be rapid and transient, occurring within 1 minute of
stimulation of cells and significantly decreasing after 5 minutes of cell
treatment. In vivo binding experiments in COS cells showed that binding of
Stat5 to the EpoR was mediated through the Stat5 Src homology 2 (SH2)
domain. In vitro binding studies further showed that Stat5, but not other
Stats examined, bound specifically to tyrosine-phosphorylated recombinant
EpoR fusion proteins. In these in vivo and in vitro binding studies, Stat5
bound, albeit to a lesser degree, to truncated EpoR mutants in which all
the intracellular tyrosines except Y-343 were removed. Furthermore,
EpoR-derived synthetic phosphotyrosine peptides corresponding to Y-343,
Y-401, Y-431, and Y-479 inhibited the in vitro binding of Stat5. When
expressed in 32D cells, a mutant EpoR in which all the intracellular
tyrosines were removed by carboxy-terminal truncation showed a
significantly impaired ability to induce tyrosine phosphorylation of Stat5,
particularly at low concentrations of Epo, but exhibited an increased
sensitivity to Epo for growth signaling as compared with the wild-type
EpoR. These results indicate that Stat5 specifically and transiently binds
to the EpoR through the interaction between the Stat5 SH2 domain and
specific phosphorylated tyrosines, including Y-343, in the EpoR cytoplasmic
domain. It was implied that betaIL3 may also have similar Stat5 docking
sites. The Stat5 docking sites in the EpoR were shown to facilitate
specific activation of Stat5, which, however, may not be required for the
EpoR-mediated growth signaling.
Volume 88,
Issue 12,
pp. 4415-4425,
12/15/1996
Copyright © 1996 by The American Society of Hematology
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