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Dissection of the cytoplasmic domains of cytokine receptors involved in STAT and Ras dependent proliferation

Oncogene volume 21, pages 3579–3591 (2002)Cite this article

Abstract

Cytokine receptors have different signaling requirements which ultimately lead to various physiological responses. In an effort to precisely characterize the molecular determinants involved in the proliferative response mediated by cytokines, we examine dose-dependent proliferation of the βc (GM-CSF, IL-3, IL-5) and homodimeric (G-CSF, TPO) cytokine receptors. Here we report that all cytokine receptors tested activate mostly STAT3 and STAT5. While STAT3 had a positive effect on βc cytokine receptor dependent proliferation, STAT5 was strongly inhibitory. Similarly, G-CSF and TPO lead to activation of STAT3 and STAT5 but, unlike the βc cytokine receptors, both stimulated cellular growth. On the other hand, Ras activation was necessary for all receptor mediated proliferation with the exception of G-CSF R. Truncated mutants of the receptors intracellular domains were used to delineate the functional domains involved in JAK/STAT and Ras activation linked to cellular growth. For instance, we revealed a critical role for the specific alpha subunit of the βc receptors in triggering receptor activation, STAT3 stimulation and proliferation, while Ras activation originates from the distal intracellular portion of the βc subunit. Finally, we showed that proximal STAT activation is the triggering event of G-CSF and TPO receptor function.

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Acknowledgements

We are thankful to B Groner for providing the STAT6 construct, J Layton for the human G-CSF receptor and A Miyajima for the human GM-CSF receptor alpha and βc subunits. We are grateful to I Macara for RasN17 and J Pessin for the Sos1 constuct. We wish to acknowledge M Brann for critical reading of the manuscript.

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  1. ACADIA Pharmaceuticals Inc., Signal Transduction Group, San Diego, 92121, California, CA, USA

    Fabrice Piu, Michael Magnani & Max E Ader

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  1. Fabrice Piu
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  2. Michael Magnani
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Correspondence to Fabrice Piu.

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Piu, F., Magnani, M. & Ader, M. Dissection of the cytoplasmic domains of cytokine receptors involved in STAT and Ras dependent proliferation. Oncogene 21, 3579–3591 (2002). https://doi.org/10.1038/sj.onc.1205444

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