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J Biol Chem, Vol. 275, Issue 11, 7887-7893, March 17, 2000
From the Erythroid cells terminally differentiate in
response to erythropoietin binding its cognate receptor. Previously we
have shown that the tyrosine kinase Lyn associates with the
erythropoietin receptor and is essential for hemoglobin synthesis in
three erythroleukemic cell lines. To understand Lyn signaling events in
erythroid cells, the yeast two-hybrid system was used to analyze
interactions with other proteins. Here we show that the
hemopoietic-specific protein HS1 interacted directly with the SH3
domain of Lyn, via its proline-rich region. A truncated HS1, bearing
the Lyn-binding domain, was introduced into J2E erythroleukemic cells
to determine the impact upon responsiveness to erythropoietin.
Truncated HS1 had a striking effect on the phenotype of the J2E
line
HS1 Interacts with Lyn and Is Critical for Erythropoietin-induced
Differentiation of Erythroid Cells*
,,,,, and
Laboratory for Cancer Medicine, Department
of Biochemistry, the University of Western Australia and Royal Perth
Hospital, WA 6001, Western Australia, Australia, the
§ Institute for Gene Therapy and Molecular Medicine,
Mount Sinai School of Medicine, New York, New York 10030, and the
¶ Molecular Biology Department, Tsukuba Research Laboratories,
Nippon Glaxo Ltd., 43, Wadai, Tsukuba-shi, Ibaraki 300-42, Japan
the cells were smaller, more basophilic than the parental
proerythoblastoid cells and had fewer surface erythropoietin receptors.
Moreover, basal and erythropoietin-induced proliferation and
differentiation were markedly suppressed. The inability of cells
containing the truncated HS1 to differentiate may be a consequence of
markedly reduced levels of Lyn and GATA-1. In addition, erythropoietin
stimulation of these cells resulted in rapid, endosome-mediated
degradation of endogenous HS1. The truncated HS1 also suppressed the
development of erythroid colonies from fetal liver cells. These data
show that disrupting HS1 has profoundly influenced the ability of
erythroid cells to terminally differentiate.
*
This work was supported by grants from the National Health
Medical Research Council (99-0596 and 98-0610), and the Cancer Foundation of Western Australia.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Laboratory for
Cancer Medicine, Level 6, MRF Bldg., Rear 50 Murray St., Perth, WA
6001, Western Australia. Tel.: (61-8)-9224-0333; Fax: (61-8)-9224-0322; E-mail: pklinken@cyllene.uwa.edu.au.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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