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BCR/ABL activates Rap1 and B-Raf to stimulate the MEK/Erk signaling pathway in hematopoietic cells.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2005 Jan 21; Vol. 326 (3), pp. 645-51. - Publication Year :
- 2005
-
Abstract
- The BCR/ABL fusion tyrosine kinase activates various intracellular signaling pathways, thus causing chronic myeloid leukemia (CML). Here we demonstrate that the inducible expression of BCR/ABL in a murine hematopoietic cell line, TonB210, leads to the activation of the Ras family small GTPase Rap1, which is inhibited by the ABL kinase inhibitor imatinib. The Rap1 activity in a CML cell line, K562, was also inhibited by imatinib. Inhibition of Rap1 activation by a dominant negative mutant of Rap1, Rap1-N17, or SPA-1 inhibited the BCR/ABL-induced activation of Elk-1. BCR/ABL also activated in a kinase activity-dependent manner the B-Raf kinase, which is an effector molecule of Rap1 and a potent activator of the MEK/Erk/Elk-1 signaling pathway. Together, these data suggest that, in addition to the well-established Ras/Raf-1 pathway, BCR/ABL activates the alternative signaling pathway involving Rap1 and B-Raf to activate Erk, which may play important roles in leukemogenesis.
- Subjects :
- Animals
Hematopoietic Stem Cells metabolism
Mice
rac GTP-Binding Proteins metabolism
ras Proteins metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
Fusion Proteins, bcr-abl metabolism
MAP Kinase Kinase Kinases metabolism
Proto-Oncogene Proteins B-raf metabolism
rap1 GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-291X
- Volume :
- 326
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 15596148
- Full Text :
- https://doi.org/10.1016/j.bbrc.2004.11.086