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Lyn Physically Associates With the Erythropoietin Receptor and May
Play a Role in Activation of the Stat5 Pathway
Hiroshi Chin,
Ayako Arai,
Hiroshi Wakao,
Ryuichi Kamiyama,
Nobuyuki Miyasaka, and
Osamu Miura
From the First Department of Internal Medicine and School of Allied
Health Sciences, Tokyo Medical and Dental University, Tokyo, Japan; and
the Helix Research Institute, Chiba, Japan.
Protein tyrosine phosphorylation plays a crucial role in signaling
from the receptor for erythropoietin (Epo), although the Epo receptor
(EpoR) lacks the tyrosine kinase domain. We have previously shown that
the Jak2 tyrosine kinase couples with the EpoR to transduce a growth
signal. In the present study, we demonstrate that Lyn, a Src family
tyrosine kinase, physically associates with the EpoR in Epo-dependent
hematopoietic cell lines, 32D/EpoR-Wt and F36E. Coexpression
experiments in COS7 cells further showed that Lyn induces tyrosine
phosphorylation of the EpoR and that both LynA and LynB, alternatively
spliced forms of Lyn, bind with the membrane-proximal 91-amino acid
region of the EpoR cytoplasmic domain. In vitro binding studies
using GST-Lyn fusion proteins further showed that the Src homology
(SH)-2 domain of Lyn specifically binds with the
tyrosine-phosphorylated EpoR in lysate from Epo-stimulated cells,
whereas the tyrosine kinase domain of Lyn binds with the unphosphorylated EpoR. Far-Western blotting and synthetic
phosphopeptide competition assays further indicated that the Lyn SH2
domain directly binds to the tyrosine-phosphorylated EpoR, most likely
through its interaction with phosphorylated Y-464 or Y-479 in the
carboxy-terminal region of the EpoR. In vitro binding studies also
demonstrated that the Lyn SH2 domain directly binds to
tyrosine-phosphorylated Jak2. In vitro reconstitution
experiments in COS7 cells further showed that Lyn induces tyrosine
phosphorylation of Stat5, mainly on Y-694, and activates the
DNA-binding and transcription-activating abilities of Stat5. In
agreement with this, Lyn enhanced the Stat5-dependent transcriptional
activation when overexpressed in 32D/EpoR-Wt cells. In addition, Lyn
was demonstrated to phosphorylate the EpoR and Stat5 on tyrosines in
vitro. These results suggest that Lyn may play a role in activation of
the Jak2/Stat5 and other signaling pathways by the EpoR.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3734-3745
© 1998 by The American Society of Hematology.
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|
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|
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|
|
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C. P. Miller, Z. Y. Liu, C. T. Noguchi, and D. M. Wojchowski
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November 15, 1999;
94(10):
3381 - 3387.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
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Y. Nosaka, A. Arai, N. Miyasaka, and O. Miura
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J. Biol. Chem.,
October 15, 1999;
274(42):
30154 - 30162.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. V. Kazansky, E. B. Kabotyanski, S. L. Wyszomierski, M. A. Mancini, and J. M. Rosen
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J. Biol. Chem.,
August 6, 1999;
274(32):
22484 - 22492.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. A. Miller, D. L. Barber, L. L. Bell, B. K. Beattie, M.-Y. Zhang, B. G. Neel, M. Yoakim, L. I. Rothblum, and J. Y. Cheung
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J. Biol. Chem.,
July 16, 1999;
274(29):
20465 - 20472.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Liang, V. J. Venema, X. Wang, H. Ju, R. C. Venema, and M. B. Marrero
Regulation of Angiotensin II-induced Phosphorylation of STAT3 in Vascular Smooth Muscle Cells
J. Biol. Chem.,
July 9, 1999;
274(28):
19846 - 19851.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Arai, Y. Nosaka, H. Kohsaka, N. Miyasaka, and O. Miura
CrkL Activates Integrin-Mediated Hematopoietic Cell Adhesion Through the Guanine Nucleotide Exchange Factor C3G
Blood,
June 1, 1999;
93(11):
3713 - 3722.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Nagata, F. Kiefer, T. Watanabe, and K. Todokoro
Activation of Hematopoietic Progenitor Kinase-1 by Erythropoietin
Blood,
May 15, 1999;
93(10):
3347 - 3354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Corey and S. M. Anderson
Src-Related Protein Tyrosine Kinases in Hematopoiesis
Blood,
January 1, 1999;
93(1):
1 - 14.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Duprez, U. Blank, S. Chretien, S. Gisselbrecht, and P. Mayeux
Physical and Functional Interaction between p72syk and Erythropoietin Receptor
J. Biol. Chem.,
December 18, 1998;
273(51):
33985 - 33990.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. C. Venema, V. J. Venema, D. C. Eaton, and M. B. Marrero
Angiotensin II-induced Tyrosine Phosphorylation of Signal Transducers and Activators of Transcription 1 Is Regulated by Janus-activated Kinase 2 and Fyn Kinases and Mitogen-activated Protein Kinase Phosphatase 1
J. Biol. Chem.,
November 13, 1998;
273(46):
30795 - 30800.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Sakamoto, T. Kitamura, and A. Yoshimura
Mitogen-activated Protein Kinase Plays an Essential Role in the Erythropoietin-dependent Proliferation of CTLL-2 Cells
J. Biol. Chem.,
November 10, 2000;
275(46):
35857 - 35862.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. von Lindern, M. P.-v. Amelsvoort, T. van Dijk, E. Deiner, E. van den Akker, S. van Emst-de Vries, P. Willems, H. Beug, and B. Lowenberg
Protein Kinase C alpha Controls Erythropoietin Receptor Signaling
J. Biol. Chem.,
October 27, 2000;
275(44):
34719 - 34727.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Arai, E. Kanda, Y. Nosaka, N. Miyasaka, and O. Miura
CrkL Is Recruited through Its SH2 Domain to the Erythropoietin Receptor and Plays a Role in Lyn-mediated Receptor Signaling
J. Biol. Chem.,
August 24, 2001;
276(35):
33282 - 33290.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
