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Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway

Oncogene volume 21, pages 2641–2651 (2002)Cite this article

Abstract

Previous studies have shown that hematopoietic cytokines, including erythropoietin (Epo) and interleukin (IL)-3, activate the Ras GTPase and the downstream Raf/Erk/Elk-1 signaling pathway. Here we report that Epo or IL-3 rapidly and transiently activates Rac, a Rho family GTPase, in hematopoietic cell lines, 32D/EpoR-Wt and UT-7. The cytokine-induced activation of Rac was augmented in a 32D/EpoR-Wt clone that inducibly overexpresses the adaptor protein CrkL or the Ras guanine nucleotide exchange factor C3G, which forms a complex with CrkL. Furthermore, the Rac activation was enhanced or inhibited in cells inducibly expressing an activated Ras mutant, H-Ras61L, or a dominant negative Ras mutant, H-Ras17N, respectively. In addition, the cytokine-induced Rac activation was inhibited by a phosphatidyl-inositol 3′-kinase (PI3K) inhibitor, LY294002, which also inhibited the Erk activation. A dominant negative Rac mutant, Rac17N, also inhibited the cytokine-induced activation of Erk as well as Elk-1. On the other hand, activation of Akt downstream of PI3K was found to play an inhibitory role in cytokine activation of Erk/Elk-1. Together, these results indicate that Rac is activated by Epo or IL-3 at downstream of the Ras/PI3K pathway in parallel with Akt and plays a role in activation of the Erk/Elk-1 signaling pathway in hematopoietic cells.

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Acknowledgements

We are grateful to Drs. Hideki Sumimoto, Yoshimi Takai, Norio Komatsu, and Michael Karin for the generous gifts of experimental materials. We also thank Dr Hideki Sumimoto for helpful discussion. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan.

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  1. Department of Hematology and Oncology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113-8519, Japan

    Ayako Arai, Eiichiro Kanda & Osamu Miura

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  1. Ayako Arai
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  2. Eiichiro Kanda
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Correspondence to Osamu Miura.

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Arai, A., Kanda, E. & Miura, O. Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway. Oncogene 21, 2641–2651 (2002). https://doi.org/10.1038/sj.onc.1205346

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