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Tyrosine 425 within the activated erythropoietin receptor binds Syp,
reduces the erythropoietin required for Syp tyrosine phosphorylation, and
promotes mitogenesis
T Tauchi, JE Damen, K Toyama, GS Feng, HE Broxmeyer and G Krystal
First Department of Internal Medicine, Tokyo Medical College, Tokyo, Japan.
Erythropoietin (Epo), the primary in vivo stimulator of erythroid
proliferation and differentiation, acts, in part, by altering the tyrosine
phosphorylation levels of various intracellular signaling molecules. These
phosphorylation levels are tightly regulated by both tyrosine kinases and
tyrosine phosphatases. We have recently shown that the SH2 containing
tyrosine phosphatase, Syp, binds directly to both the tyrosine
phosphorylated form of the Epo receptor (EpoR) and to Grb2 after Epo
stimulation of M07e cells engineered to express high levels of human EpoRs
(T. Tauchi, et al: J Biol Chem 270:5631, 1995). To determine which tyrosine
within the EpoR is responsible for binding Syp, we examined DA-3 cell lines
expressing full-length mutant EpoRs bearing tyrosine to phenylalanine
substitutions for each of the eight tyrosines within the intracellular
domain of the EpoR. We found that: (1) all Epo-stimulated mutant EpoRs,
except for the Y425F EpoR, coimmunoprecipitated with Syp; (2) all
Epo-stimulated mutant EpoRs, except for the Y425F EpoR, bound to a
GST-fusion protein containing both SH2 domains of Syp; (3) Jak2 could
phosphorylate GST-Syp in vitro after Epo stimulation of wild-type (wt) EpoR
expressing DA-3 cells; (4) Epo-stimulated tyrosine phosphorylation of Syp
in vivo was markedly reduced in Y425F EpoR expressing DA-3 calls; and (5)
DA-3 cells expressing the Y425F EpoR grow less well in response to Epo than
wt EpoR expressing cells. These results suggest that Syp binds via its SH2
domains to phosphorylated Y425 within the EpoR and is then phosphorylated
on tyrosine residues by Jak2. Moreover, Y425 in the EpoR reduces the Epo
requirement for Syp tyrosine phosphorylation and promotes proliferation.
Volume 87,
Issue 11,
pp. 4495-4501,
06/01/1996
Copyright © 1996 by The American Society of Hematology
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