BCR/ABL activates Rap1 and B-Raf to stimulate the MEK/Erk signaling pathway in hematopoietic cells.
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.
Mizuchi
Daisuke
D
Department of Hematology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Kurosu
Tetsuya
T
Kida
Aiko
A
Jin
Zhen-Hua
ZH
Jin
Aishun
A
Arai
Ayako
A
Miura
Osamu
O
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D016044:Fusion Proteins, bcr-abl; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D020744:rac GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins