|
|
Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-01-0177.
 Previous Article | Table of Contents | Next Article 
Blood, 1 February 2003, Vol. 101, No. 3, pp. 1094-1102
NEOPLASIA
Necessity of tyrosine 719 and phosphatidylinositol
3'-kinase-mediated signal pathway in constitutive activation and
oncogenic potential of c-kit receptor tyrosine kinase with
the Asp814Val mutation
Koji Hashimoto,
Itaru Matsumura,
Tohru Tsujimura,
Dae-Ki Kim,
Hideki Ogihara,
Hirokazu Ikeda,
Shuji Ueda,
Masao Mizuki,
Hiroyuki Sugahara,
Hirohiko Shibayama,
Yukihiko Kitamura, and
Yuzuru Kanakura
From the Department of Pathology and the Department of
Hematology and Oncology, Osaka University Graduate School of Medicine,
Suita; and the Department of Pathology, Hyogo College of Medicine,
Nishinomiya, Japan.
Substitution of valine (Val) for aspartic acid (Asp)
at codon 814 constitutively activates murine c-kit receptor
tyrosine kinase (KIT), and Asp816Val mutation, corresponding to murine Asp814Val mutation, is found in patients with mastocytosis and acute
myelocytic leukemia. However, the signal transduction pathways responsible for oncogenesis by the Asp814Val mutant
(KITVal814) are not fully understood. To examine the
oncogenic signal transduction of KITVal814, we converted 20 tyrosine (Tyr) residues to phenylalanine (Phe) in the cytoplasmic
domain of KITVal814 or deleted the C-terminal region
containing 2 other tyrosine residues (Del). Among various
KITVal814- derived mutants,
KITVal814-Tyr719Phe and KITVal814-Del
severely impaired receptor tyrosine phosphorylation and association with the p85 subunit of phosphatidylinositol 3'-kinase (p85
PI3-K). Moreover, KITVal814-Tyr719Phe
and KITVal814-Del failed to induce ligand-independent
growth in Ba/F3 cells, indicating that Tyr719, the binding site for
p85PI3-K, and the C-terminal region are indispensable for
factor-independent growth by KITVal814. Although the
C-terminal region was also required for ligand-dependent growth by
wild-type KIT (KITWT), the Tyr719Phe substitution
had negligible effects on ligand-dependent growth by
KITWT. Furthermore, dominant-negative PI3-K significantly
inhibited ligand-independent growth by KITVal814. These
results demonstrate that Tyr719 is crucial for constitutive activation
of KITVal814, but not for the ligand-induced activation of
KITWT, and that the downstream signaling of PI3-K plays an
important role in ligand-independent growth and tumorigenicity by
KITVal814, thereby suggesting that KITVal814 is
a unique activating mutation that leads to a distinguishable function
from the effects of KITWT.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
V. Munugalavadla, E. C. Sims, J. Borneo, R. J. Chan, and R. Kapur
Genetic and pharmacologic evidence implicating the p85{alpha}, but not p85{beta}, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis
Blood,
September 1, 2007;
110(5):
1612 - 1620.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Tefferi
Mutant Kit: thwarting the message down below
Blood,
March 15, 2005;
105(6):
2240 - 2241.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lennartsson, T. Jelacic, D. Linnekin, and R. Shivakrupa
Normal and Oncogenic Forms of the Receptor Tyrosine Kinase Kit
Stem Cells,
January 1, 2005;
23(1):
16 - 43.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Lefevre, A.-L. Glotin, A. Calipel, F. Mouriaux, T. Tran, Z. Kherrouche, C.-A. Maurage, C. Auclair, and F. Mascarelli
Roles of Stem Cell Factor/c-Kit and Effects of Glivec(R)/STI571 in Human Uveal Melanoma Cell Tumorigenesis
J. Biol. Chem.,
July 23, 2004;
279(30):
31769 - 31779.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Shivakrupa, A. Bernstein, N. Watring, and D. Linnekin
Phosphatidylinositol 3'-Kinase Is Required for Growth of Mast Cells Expressing the Kit Catalytic Domain Mutant
Cancer Res.,
August 1, 2003;
63(15):
4412 - 4419.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
