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  • Original Paper
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Repression of c-Cbl leads to enhanced G-CSF Jak-STAT signaling without increased cell proliferation

Oncogene volume 21, pages 5346–5355 (2002)Cite this article

Abstract

Engagement of the Granulocyte-Colony-Stimulating Factor (G-CSF) receptor activates non-receptor protein tyrosine kinases Lyn and Jak2. We found that Lyn-deficient DT40 cells that express the G-CSF receptor (DT40GR) do not demonstrate G-CSF-induced mitogenic signaling. Lyn associates with and phosphorylates a small set of molecules, including c-Cbl. c-Cbl is an adaptor involved in cell growth and cytoskeletal reorganization, predominantly in hematopoietic cells. Using yeast two-hybrid analysis, we found that c-Cbl directly couples Lyn to PI 3-kinase. We also found that expression of the c-CblY731F mutant, which uncouples PI 3-kinase, resulted in the inhibition of G-CSF-induced proliferative signaling in DT40GR cells. As a complementary strategy, we sought to analyse the effects of c-Cbl deficiency in DT40GR cells. We isolated, cloned and sequenced the full-length cDNA for chicken c-Cbl and constructed antisense vectors. Antisense inhibition of c-Cbl expression in DT40GR cells led to enhanced Jak-STAT activation following G-CSF stimulation. Yet, this enhancement of Jak-STAT activation was associated with decreased G-CSF-induced PI 3-kinase activity and DNA synthesis. PI 3-kinase activity correlated with DNA synthesis and physiological levels of c-Cbl. Together, these data suggest that physiologic level of c-Cbl provides a growth stimulatory pathway for G-CSF and that enhanced Jak-STAT activation is not sufficient for G-CSF-induced growth.

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Authors and Affiliations

  1. Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Lin Wang, William A Rudert, Inna Loutaev, Vera Roginskaya & Seth J Corey

  2. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Seth J Corey

  3. Division of Hematology-Oncology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Seth J Corey

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  1. Lin Wang
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  2. William A Rudert
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  3. Inna Loutaev
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  4. Vera Roginskaya
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  5. Seth J Corey
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Correspondence to Seth J Corey.

Additional information

The full-length nucleotide sequence of the chicken c-Cbl cDNA has been registered as GenBank accession number AF318895.

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Wang, L., Rudert, W., Loutaev, I. et al. Repression of c-Cbl leads to enhanced G-CSF Jak-STAT signaling without increased cell proliferation. Oncogene 21, 5346–5355 (2002). https://doi.org/10.1038/sj.onc.1205670

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