Transformation of Myeloid Leukemia Cells to Cytokine Independence by Bcr-Abl Is Suppressed by Kinase-defective Hck
Open Access
- 1 June 2000
- journal article
- Published by Elsevier BV
- Vol. 275 (24), 18581-18585
- https://doi.org/10.1074/jbc.c000126200
Abstract
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 beta-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.Keywords
This publication has 32 references indexed in Scilit:
- Src Family Tyrosine Kinases and Growth Factor SignalingExperimental Cell Research, 2000
- Chronic Myeloid LeukemiaNew England Journal of Medicine, 1999
- The function of BCR/ABL and related proto-oncogenesCurrent Opinion in Hematology, 1997
- P210 and P190 Induce the Tyrosine Phosphorylation and DNA Binding Activity of Multiple Specific STAT Family MembersPublished by Elsevier BV ,1996
- The CRKL Adaptor Protein Transforms Fibroblasts and Functions in Transformation by the BCR-ABL OncogenePublished by Elsevier BV ,1996
- Autophosphorylation of the Fes Tyrosine KinasePublished by Elsevier BV ,1996
- Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl.The Journal of Experimental Medicine, 1996
- Induction of Chronic Myelogenous Leukemia in Mice by the P210
bcr/abl
Gene of the Philadelphia ChromosomeScience, 1990
- Fused transcript of abl and bcr genes in chronic myelogenous leukaemiaNature, 1985
- Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22Cell, 1984