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A new feature of Mpl receptor: ligand-induced transforming activity in FRE rat fibroblasts

Oncogene volume 19, pages 2033–2042 (2000)Cite this article

Abstract

Mpl is the receptor for thrombopoietin, the primary regulator of platelet production by megakaryocytes. Upon stimulation by its ligand, Mpl receptor induces proliferation and differentiation of hematopoietic cell lines of various origins. In this paper, we show that Mpl is also able to transform FRE rat fibroblasts in the presence of MGDF (pegylated Megakaryocyte Growth and Development Factor), a modified form of its ligand. We also demonstrate that upon MGDF stimulation Mpl receptor activates the classical transduction pathways described for hematopoietic cell lines in FRE cells. Introduction of Mpl deletion mutants in FRE cells allowed us to demonstrate that the C-terminal region of the Mpl intracytoplasmic domain, which is involved in hematopoietic differentiation, is necessary for the transformation process. Within that region, site-directed mutagenesis showed that the Y112 residue, which is required for Shc phosphorylation, is essential for rat fibroblast transformation by Mpl/MGDF, suggesting the involvement of Shc in Mpl-mediated transformation. Interestingly, we showed that transformation correlated with strong and sustained MAPK activation. Neither Jak2, Stat3 nor Stat5 phosphorylation was sufficient to induce the transformation process. Taken altogether, our results suggest the oncogenicity of Mpl in fibroblastic cells in the presence of its ligand.

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Acknowledgements

We thank Dr P Mayeux, Dr F Morlé and F Verdier for helpful discussions and support during this study, and Patricia Albanese for her help in engineering the point mutations in Mp1 receptor. We are grateful to Drs JP Rosa, F Gouilleux and B Péault for critical reading of the manuscript. We also gratefully acknowledge I Bouchaert (ICGM) for help with the cytometry analysis. PEG-rhMGDF was provided by Amgen (Thousand Oaks, CA, USA). This work was supported by INSERM (Institut National de la Recherche Médicale). C Challier is supported by the Ministère de l'Education de la Recherche et de la Technologie (MERT).

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  1. Institut National de la Santé et de la Recherche Médicale, U506, Hôpital Paul Brousse, Villejuif Cedex, 94807, France

    C Challier, L Cocault & M Souyri

  2. U363, Institut Cochin de Génétique Moléculaire, Hôpital Cochin, Paris, 75014, France

    C Challier, L Cocault, M Flon, M Pauchard, F Porteu, S Gisselbrecht & M Souyri

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  1. C Challier
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Challier, C., Cocault, L., Flon, M. et al. A new feature of Mpl receptor: ligand-induced transforming activity in FRE rat fibroblasts. Oncogene 19, 2033–2042 (2000). https://doi.org/10.1038/sj.onc.1203472

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