|
|
 Previous Article | Table of Contents | Next Article 
Blood, 15 August 2002, Vol. 100, No. 4, pp. 1438-1448
NEOPLASIA
TEL-JAK2 constitutively activates the extracellular
signal-regulated kinase (ERK), stress-activated protein/Jun kinase
(SAPK/JNK), and p38 signaling pathways
Jenny M.-Y. Ho,
Melody
H.-H. Nguyen,
Jamil K. Dierov,
Karla M. Badger,
Bryan K. Beattie,
Piero Tartaro,
Rizwan Haq,
Brent W. Zanke,
Martin P. Carroll, and
Dwayne L. Barber
From the Division of Cellular and Molecular Biology and
Division of Experimental Therapeutics, Ontario Cancer Institute,
University Health Network; Departments of Medical Biophysics and
Laboratory Medicine and Pathobiology, Institute of Medical Science,
University of Toronto; and Department of Laboratory Medicine and
Pathobiology, Toronto General Hospital, University Health Network; all
of Toronto, Ontario, Canada; Cross Cancer Institute, Edmonton, AB; and
Division of Hematology and Oncology, University of Pennsylvania,
Philadelphia, PA.
The ets transcription factor, TEL, undergoes
chromosomal rearrangements with the tyrosine kinase JAK2. TEL-JAK2 is
constitutively active, confers cell line factor independence, and
activates signal transducer and activator of transcription-1 (STAT1),
STAT3, and STAT5. Data from bone marrow transplantation models suggest
that STAT5 activation does not account for the entire disease phenotype induced by TEL-JAK2. This study examined additional signaling pathways
that are activated by TEL-JAK2. TEL-JAK2 expression in Ba/F3 cells
results in constitutive association and tyrosine phosphorylation of Shc
and Ship-1 and, consequently, recruitment of Grb2 to TEL-JAK2. Direct
Grb2 recruitment is also possible because a putative Grb2 binding site,
Tyr314, is present on TEL-JAK2(5-19) and TEL-JAK2(5-12). Studies
with a TEL-JAK2(5-19)Tyr314Phe mutant support a role for Tyr314
in Grb2 recruitment, because Grb2 association with
TEL-JAK2(5-19)Tyr314Phe is significantly reduced. Interestingly,
TEL-JAK2(5-19)Tyr314Phe shows reduced Ras activation when
compared with TEL-JAK2(4-17), TEL-JAK2(5-12), and TEL-JAK2(5-19).
Analysis of extracellular signal-regulated kinase-1/2 (ERK1/2),
stress-activated protein/Jun kinase (SAPK/JNK), and p38
demonstrates the activation of SAPK/JNK and phosphorylation of p38 by
all TEL-JAK2 isoforms. TEL-JAK2(5-12) and TEL-JAK2(5-19) preferentially
phosphorylate ERK2, whereas TEL-JAK2(4-17) phosphorylated ERK2 at lower
levels. Inhibition studies demonstrated that ERK1/2 activation was
necessary for Ba/F3 factor independence mediated by TEL-JAK2(5-19),
while inhibition of SAPK/JNK or p38 activity had no effect. Our data
reveal the requirement of ERK activation by TEL-JAK2(5-19) in Ba/F3
cells and suggest that TEL-JAK2 leukemogenic potential may be mediated in part through ERK1/2.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
N. Harir, C. Pecquet, M. Kerenyi, K. Sonneck, B. Kovacic, R. Nyga, M. Brevet, I. Dhennin, V. Gouilleux-Gruart, H. Beug, et al.
Constitutive activation of Stat5 promotes its cytoplasmic localization and association with PI3-kinase in myeloid leukemias
Blood,
February 15, 2007;
109(4):
1678 - 1686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Kennedy, F. Barabe, B. J. Patterson, J. Bayani, J. A. Squire, D. L. Barber, and J. E. Dick
Expression of TEL-JAK2 in primary human hematopoietic cells drives erythropoietin-independent erythropoiesis and induces myelofibrosis in vivo
PNAS,
November 7, 2006;
103(45):
16930 - 16935.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. O. Flowers, H. M. Johnson, M. G. Mujtaba, M. R. Ellis, S. M. I. Haider, and P. S. Subramaniam
Characterization of a Peptide Inhibitor of Janus Kinase 2 That Mimics Suppressor of Cytokine Signaling 1 Function
J. Immunol.,
June 15, 2004;
172(12):
7510 - 7518.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. P. Million, N. Harakawa, S. Roumiantsev, L. Varticovski, and R. A. Van Etten
A Direct Binding Site for Grb2 Contributes to Transformation and Leukemogenesis by the Tel-Abl (ETV6-Abl) Tyrosine Kinase
Mol. Cell. Biol.,
June 1, 2004;
24(11):
4685 - 4695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Wheadon and M. J. Welham
The coupling of TEL/PDGF{beta}R to distinct functional responses is modulated by the presence of cytokine: involvement of mitogen-activated protein kinases
Blood,
August 15, 2003;
102(4):
1480 - 1489.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
