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Involvement of Shc and Cbl-PI 3-kinase in Lyn-dependent proliferative signaling pathways for G-CSF

Oncogene volume 19, pages 97–105 (2000)Cite this article

Abstract

Granulocyte colony-stimulating factor (G-CSF) is the major hematopoietic factor which controls the production and differentiation of granulocytes. The G-CSF receptor (G-CSFR) belongs to the superfamily of the cytokine receptors, which transduce signals via the activation of cytosolic protein tyrosine kinases (PTK). To determine the role of specific PTK in G-CSF signaling we expressed the human G-CSFR in cell lines derived from DT40 B cells, which lack either the Src-related Lyn or Syk. Wild-type (wt) and syk-deficient cells underwent increased DNA synthesis in response to G-CSF; lyn-deficient cells did not. The purpose of these studies is to identify Lyn's downstream effectors in mediating DNA synthesis. While G-CSF stimulated Ras activity in all cell lines, G-CSF failed to induce the tyrosine phosphorylation of Shc in lyn-deficient cells. G-CSF induced a statistically significant activation of Erk1/Erk2 Kinase or p90Rsk only in the wt cells. G-CSF induced the tyrosine phosphorylation of Cbl and increased activity of PI 3-kinase in wild-type and syk-deficient, but non in lyn-deficient, cells. Inhibition of Shc by over-expression of its SH2 or PTB domains or PI 3-kinase by either treatment with wortmannin or expression of the CblY731F mutant decreased G-CSF-induced DNA synthesis. Thus, the Lyn, Cbl-PI 3-kinase, and Shc/non-Ras-dependent pathways correlate with the ability of cells to respond to G-CSF with increased DNA synthesis.

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Acknowledgements

Supported by grants from the American Cancer Society (SJ Corey), Blood Science Foundation of the Institute for Transfusion Medicine (SJ Corey), Kevin Hnatt Fund (SJ Corey), Bear Necessities Foundation (SJ Corey), and National Institutes of Health (SJ Corey, J Gomez-Cambronero), and American Heart Association (J Gomez-Cambronero). The authors thank Drs John O'Bryan, Jane McClade, and Hisamaru Hirai for the Shc and Cbl constructs. The authors thank Dr Igor Semenov for data analysis.

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Authors and Affiliations

  1. Division of Hematology-Oncology, Children's Hospital of Pittsburgh, Pittsburgh, 15213, Pennsylvania, PA, USA

    Anatoly Grishin, Srish Sinha, Vera Roginskaya, Michael J Boyer, Sherry Zuo, Guillermo Romero & Seth J Corey

  2. Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, 45401, Ohio, OH, USA

    Julian Gomez-Cambronero

  3. Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570, Japan

    Tomohiro Kurosaki

  4. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, 15213, Pennsylvania, PA, USA

    Seth J Corey

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  1. Anatoly Grishin
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Grishin, A., Sinha, S., Roginskaya, V. et al. Involvement of Shc and Cbl-PI 3-kinase in Lyn-dependent proliferative signaling pathways for G-CSF. Oncogene 19, 97–105 (2000). https://doi.org/10.1038/sj.onc.1203254

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