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.
From: Department of Hematology, Tokyo Medical and Dental University, Japan.
Oncogene
- Publish Date: Jul 2006
- ISSN: 0950-9232
- Volume: 25
- Issue: 31
- Pages: 4332-40
- Medium: Print
- Language: English
- Citation (JAMA): Jin A, Kurosu T, Tsuji K, et al. 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.. Oncogene Jul 2006;25:4332-40
Abstract
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.
Mesh Headings (Keywords): Animals, Apoptosis, Cell Adhesion, Cell Line, Cell Proliferation, Clone Cells, Extracellular Signal-Regulated MAP Kinases, Fusion Proteins, bcr-abl, Humans, Interleukin-3, K562 Cells, MAP Kinase Kinase 1, Mice, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Signal Transduction, Tumor Cells, Cultured, rap1 GTP-Binding Proteins
Check for Full Text / PubMed Unique Identifier (PMID): 16518411
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