|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1319-1329
Activating Mutation in the Catalytic Domain of c-kit Elicits
Hematopoietic Transformation by Receptor Self-Association Not at the
Ligand-Induced Dimerization Site
Tohru Tsujimura,
Koji Hashimoto,
Hitoshi Kitayama,
Hirokazu Ikeda,
Hiroyuki Sugahara,
Itaru Matsumura,
Tsuneyasu Kaisho,
Nobuyuki Terada,
Yukihiko Kitamura, and
Yuzuru Kanakura
From The Departments of Pathology and Hematology/Oncology, Osaka
University Medical School, Suita, Osaka, Japan; and the First
Department of Pathology and Institute for Advanced Medical Sciences,
Laboratory of Host Defenses, Hyogo College of Medicine, Hyogo, Japan.
The c-kit receptor tyrosine kinase (KIT) is constitutively
activated by naturally occurring mutations in either the juxtamembrane domain or the kinase domain. Although the juxtamembrane domain mutations led to ligand-independent KIT dimerization, the kinase domain
mutations (Asp814  Val or Tyr) did not.
In an effort to determine if the kinase domain mutant could transfer
oncogenic signaling without receptor dimerization, we have constructed
the truncated types of c-kitWild and
c-kitTyr814 cDNAs
(c-kitDel-Wild and
c-kitDel-Tyr814 cDNAs, respectively), in which
ligand-binding and ligand-induced dimerization domains were deleted.
When c-kitDel-Wild and
c-kitDel-Tyr814 genes were introduced into a murine
interleukin-3 (IL-3)-dependent cell line Ba/F3,
KITDel-Tyr814 was constitutively phosphorylated on tyrosine
and activated, whereas KITDel-Wild was not. In addition,
Ba/F3 cells expressing KITDel-Tyr814
(Ba/F3Del-Tyr814) grew in suspension culture without the
addition of exogenous growth factor, whereas Ba/F3 cells expressing
KITDel-Wild (Ba/F3Del-Wild) required
IL-3 for growth. The factor-independent growth of
Ba/F3Del-Tyr814 cells was virtually abrogated by
coexpression of KITW42 that is a dominant-negative form
of KIT, but not by that of KITWild, suggesting that
KITDel-Tyr814 may not function as a monomer but may require
receptor dimerization for inducing factor-independent growth.
Furthermore, KITDel-Tyr814 was found to be
coimmunoprecipitated with KITWild or KITW42 by
an ACK2 monoclonal antibody directed against the extracellular domain
of KIT. Moreover, KITW42 was constitutively associated with
a chimeric FMS/KITTyr814 receptor containing the
ligand-binding and receptor dimerization domain of c-fms
receptor (FMS) fused to the transmembrane and cytoplasmic domain of
KITTyr814, but not with a chimeric FMS/KITWild
receptor even after stimulation with FMS-ligand. These results suggest
that constitutively activating mutation of c-kit at the Asp814 codon may cause a conformation change that leads to
receptor self-association not in the extracellular domain and that the receptor self-association of the Asp814 mutant may be
important for activation of downstream effectors that are required for
factor-independent growth and tumorigenicity.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
H. Bougherara, F. Subra, R. Crepin, P. Tauc, C. Auclair, and M.-A. Poul
The Aberrant Localization of Oncogenic Kit Tyrosine Kinase Receptor Mutants Is Reversed on Specific Inhibitory Treatment
Mol. Cancer Res.,
September 1, 2009;
7(9):
1525 - 1533.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. P. Rocconi, K. S. Matthews, K. J. Kimball, M. G. Conner, A. C. Baker, and M. N. Barnes
Expression of C-kit and Platelet-Derived Growth Factor Receptors in Ovarian Granulosa Cell Tumors
Reproductive Sciences,
September 1, 2008;
15(7):
673 - 677.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. Mayerhofer, K. V. Gleixner, A. Hoelbl, S. Florian, G. Hoermann, K. J. Aichberger, M. Bilban, H. Esterbauer, M.-T. Krauth, W. R. Sperr, et al.
Unique Effects of KIT D816V in BaF3 Cells: Induction of Cluster Formation, Histamine Synthesis, and Early Mast Cell Differentiation Antigens
J. Immunol.,
April 15, 2008;
180(8):
5466 - 5476.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Florian, M. Ghannadan, M. Mayerhofer, K. J. Aichberger, A. W. Hauswirth, G.-H. Schernthaner, D. Printz, G. Fritsch, A. Bohm, K. Sonneck, et al.
Evaluation of normal and neoplastic human mast cells for expression of CD172a (SIRP{alpha}), CD47, and SHP-1
J. Leukoc. Biol.,
June 1, 2005;
77(6):
984 - 992.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hashimoto, I. Matsumura, T. Tsujimura, D.-K. Kim, H. Ogihara, H. Ikeda, S. Ueda, M. Mizuki, H. Sugahara, H. Shibayama, et al.
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
Blood,
February 1, 2003;
101(3):
1094 - 1102.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Szymkiewicz, K. Kowanetz, P. Soubeyran, A. Dinarina, S. Lipkowitz, and I. Dikic
CIN85 Participates in Cbl-b-mediated Down-regulation of Receptor Tyrosine Kinases
J. Biol. Chem.,
October 11, 2002;
277(42):
39666 - 39672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Frost, P. T. Ferrao, T. P. Hughes, and L. K. Ashman
Juxtamembrane Mutant V560GKit Is More Sensitive to Imatinib (STI571) Compared with Wild-Type c-Kit Whereas the Kinase Domain Mutant D816VKit Is Resistant
Mol. Cancer Ther.,
October 1, 2002;
1(12):
1115 - 1124.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Heinrich, C. D. Blanke, B. J. Druker, and C. L. Corless
Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies
J. Clin. Oncol.,
March 15, 2002;
20(6):
1692 - 1703.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Jahn, P. Seipel, S. Urschel, C. Peschel, and J. Duyster
Role for the Adaptor Protein Grb10 in the Activation of Akt
Mol. Cell. Biol.,
February 15, 2002;
22(4):
979 - 991.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Miranda, M. Di Virgilio, S. Selleri, G. Zanotti, S. Pagliardini, M. A. Pierotti, and A. Greco
Novel Pathogenic Mechanisms of Congenital Insensitivity to Pain with Anhidrosis Genetic Disorder Unveiled by Functional Analysis of Neurotrophic Tyrosine Receptor Kinase Type 1/Nerve Growth Factor Receptor Mutations
J. Biol. Chem.,
February 15, 2002;
277(8):
6455 - 6462.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-Q. Ning, J. Li, and R. J. Arceci
Signal transducer and activator of transcription 3 activation is required for Asp816 mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells
Blood,
June 1, 2001;
97(11):
3559 - 3567.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Mardy, Y. Miura, F. Endo, I. Matsuda, and Y. Indo
Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor
Hum. Mol. Genet.,
February 1, 2001;
10(3):
179 - 188.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mizuki, R. Fenski, H. Halfter, I. Matsumura, R. Schmidt, C. Muller, W. Gruning, K. Kratz-Albers, S. Serve, C. Steur, et al.
Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways
Blood,
December 1, 2000;
96(12):
3907 - 3914.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Xiao, J. G. McCarthy, J. C. Aster, and J. A. Fletcher
ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain
Blood,
July 15, 2000;
96(2):
699 - 704.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
