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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 volume 25, pages 4332–4340 (2006)Cite this article

Abstract

The Ras family small GTPase Rap1 is activated by hematopoietic cytokines, such as interleukin (IL)-3, to induce β1 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.

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Acknowledgements

We are grateful to Drs George Q Daley, and Johannes L Bos for the generous gifts of experimental materials. This study was supported in part by grants from Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Hematology, Tokyo Medical and Dental University, Tokyo, Japan

    A Jin, T Kurosu, K Tsuji, D Mizuchi, A Arai & O Miura

  2. Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan

    H Fujita, M Hattori & N Minato

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  1. A Jin
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  2. T Kurosu
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Correspondence to O Miura.

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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 25, 4332–4340 (2006). https://doi.org/10.1038/sj.onc.1209459

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