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J. Biol. Chem., Vol. 275, Issue 24, 18581-18585, June 16, 2000
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From the Department of Molecular Genetics and Biochemistry,
University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania 15261
Bcr-Abl is the constitutively active
protein-tyrosine kinase expressed as a result of the Philadelphia
translocation in chronic myelogenous leukemia. Bcr-Abl is coupled to
many of the same signaling pathways normally regulated by hematopoietic
cytokines. Recent work shows that Hck, a member of the Src tyrosine
kinase family with myeloid-restricted expression, associates with and
is activated by Bcr-Abl. Here we investigated the mechanism of Hck
interaction with Bcr-Abl and the requirement for Hck activation in
Bcr-Abl transformation signaling. Binding studies demonstrated that the Hck SH3 and SH2 domains are sufficient for interaction with Bcr-Abl in vitro. Hck binding localizes to the Abl SH2, SH3, and
kinase domains as well as the distal portion of the C-terminal tail. To
address the requirement for endogenous Src family kinase activation in
Bcr-Abl signaling, a kinase-defective mutant of Hck was stably expressed in the cytokine-dependent myeloid leukemia cell
line DAGM. Kinase-defective Hck dramatically suppressed Bcr-Abl-induced outgrowth of these cells in the absence of cytokine compared with a
control cell line expressing
ACCELERATED PUBLICATION
Transformation of Myeloid Leukemia Cells to Cytokine Independence
by Bcr-Abl Is Suppressed by Kinase-defective Hck*
,
-galactosidase. In contrast,
kinase-defective Hck did not affect cell proliferation in response to
interleukin-3, suggesting that the effect is specific for Bcr-Abl.
These data show that Hck interacts with Bcr-Abl through a complex
mechanism involving kinase-dependent and -independent
components and that interaction with Hck or other Src family members is
essential for transformation signaling by Bcr-Abl.
*
This work was supported by National Institutes of Health
Grant CA81398 and American Cancer Society Grant RPG-96-052-04-TBE.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.
Present address: Dept. of Pathology and Microbiology, University
of Nebraska Medical Center, Omaha, NE 68198.
§
To whom correspondence should be addressed: Dept. of Molecular
Genetics and Biochemistry, University of Pittsburgh School of Medicine,
E1240 Biomedical Science Tower, Pittsburgh, PA 15261. Tel.:
412-648-9495; Fax: 412-624-1401; E-mail: tsmithga@pitt.edu.
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