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Mitogenic synergy through multilevel convergence of hepatocyte growth factor and interleukin-4 signaling pathways

Oncogene volume 21, pages 2201–2211 (2002)Cite this article

Abstract

Hepatocyte growth factor (HGF) regulates various physiological and developmental processes in concert with other growth factors, cytokines and hormones. We examined interactions between cell signaling events elicited by HGF and the cytokine interleukin (IL)-4, in the IL-3-dependent murine myeloid cell line 32D transfected with the human HGF receptor, c-Met. HGF was a potent mitogen in these cells, and prevented apoptosis in response to IL-3 withdrawal. IL-4 showed modest anti-apoptotic activity, but no significant mitogenic activity. IL-4 synergistically enhanced HGF-stimulated DNA synthesis, whereas only additive prevention of apoptosis was observed. IL-4 did not enhance HGF-dependent tyrosine phosphorylation of c-Met or Shc. In contrast, HGF-stimulated activation of MAP kinases was enhanced by IL-4, suggesting that the IL-4 and HGF signaling pathways converge upstream of these events. Although phosphatidylinositol 3-kinase (PI3K) inhibitors diminished HGF-induced mitogenesis, anti-apoptosis, and MAP kinase activation, IL-4 enhanced HGF signaling persisted even in the presence of these inhibitors. IL-4 enhancement of HGF signaling was partially blocked in 32D/c-Met cells treated with inhibitors of MEK1 or c-Src kinases, completely blocked by expression of a catalytically inactive mutant of Janus kinase 3 (Jak3), and increased in 32D/c-Met cells overexpressing STAT6. Our results suggest that the IL-4 and HGF pathways converge at multiple levels, and that IL-4-dependent Jak3 and STAT6 activities modulate signaling events independent of PI3K to enhance HGF-dependent mitogenesis in myeloid cells, and possibly other common cellular targets.

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Acknowledgements

We thank Drs Jacalyn Pierce, Jeffrey Rubin, William Taylor, William LaRochelle, and Yuichiro Suzuki for helpful discussions. We also thank Nelson Ellmore for technical assistance.

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Authors and Affiliations

  1. Division of Basic Sciences, Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Regina M Day, Lilian Soon, Diane Breckenridge, Benjamin Bridges, Bharvin K R Patel, Ling Mei Wang, Seth J Corey & Donald P Bottaro

  2. Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Regina M Day, Lilian Soon, Diane Breckenridge, Benjamin Bridges, Bharvin K R Patel, Ling Mei Wang, Seth J Corey & Donald P Bottaro

  3. Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Regina M Day, Lilian Soon, Diane Breckenridge, Benjamin Bridges, Bharvin K R Patel, Ling Mei Wang & Donald P Bottaro

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Correspondence to Donald P Bottaro.

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Day, R., Soon, L., Breckenridge, D. et al. Mitogenic synergy through multilevel convergence of hepatocyte growth factor and interleukin-4 signaling pathways. Oncogene 21, 2201–2211 (2002). https://doi.org/10.1038/sj.onc.1205289

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