BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion.
The Ras family small GTPase Rap1 is activated by hematopoietic cytokines, such as interleukin (IL)-3, to induce beta1 integrin-mediated cell adhesion or by the BCR/ABL fusion tyrosine kinase to stimulate the MEK/Erk signaling pathway. Here, we demonstrate that the abrogation of Rap1 activation by SPA-1, a Rap1-specific GAP, inhibits activation of B-Raf, MEK, Erk, and Akt in a murine hematopoietic cell line, Ton.B210, stimulated with IL-3 or inducibly expressing BCR/ABL. Furthermore, Rap1 inactivation had an inhibitory effects on proliferation and survival of Ton.B210 cells, which were more remarkable when cells were stimulated by BCR/ABL than by IL-3. Induction of BCR/ABL expression increased adhesion of Ton.B210 cells to fibronectin in a manner at least partly dependent on its kinase activity, and Rap1 inhibition by SPA-1 partially inhibited BCR/ABL-induced adhesion of cells. Thus, IL-3- or BCR/ABL-induced activation of Rap1 may play important roles in regulation of cell proliferation and survival through activation of the B-Raf/MEK/Erk and Akt signaling pathways and in induction of integrin-mediated cell adhesion. Furthermore, as compared with IL-3, BCR/ABL is more dependent on Rap1-mediated signaling to induce cell proliferation and survival and, thus, Rap1 may represent an attractive target for novel therapies for leukemias caused by BCR/ABL.
Jin
A
A
Department of Hematology, Tokyo Medical and Dental University, Japan.
Kurosu
T
T
Tsuji
K
K
Mizuchi
D
D
Arai
A
A
Fujita
H
H
Hattori
M
M
Minato
N
N
Miura
O
O
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D002999:Clone Cells; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000502:physiology*; D020014:K562 Cells; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D007377:Interleukin-3; D016044:Fusion Proteins, bcr-abl; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D020827:rap1 GTP-Binding Proteins