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

Day, R. M., Soon, L., Breckenridge, D., Bridges, B., Patel, B. K., Wang, L. M., Corey, S. J. and Bottaro, D. P. (2002) Mitogenic synergy through multilevel convergence of hepatocyte growth factor and interleukin-4 signaling pathways. Oncogene, 21 (14). pp. 2201-11. ISSN 0950-9232

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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.

Item Type: Article
Additional Information: 0950-9232 Journal Article GDSC130
Keywords: 1-Phosphatidylinositol 3-Kinase/metabolism *Adaptor Proteins, Signal Transducing *Adaptor Proteins, Vesicular Transport Animals Apoptosis/drug effects Dose-Response Relationship, Drug Drug Synergism Hepatocyte Growth Factor/*pharmacology Hepatocytes/cytology/drug effects Interleukin-3/pharmacology Interleukin-4/antagonists & inhibitors/*pharmacology MAP Kinase Kinase 1 Mice Mitogen-Activated Protein Kinase Kinases/metabolism Mitogen-Activated Protein Kinases/metabolism Mitogens/*pharmacology Protein-Serine-Threonine Kinases/metabolism Protein-Tyrosine Kinase/metabolism Proteins/antagonists & inhibitors/metabolism Proto-Oncogene Protein c-met/metabolism Signal Transduction/*drug effects Time Factors Trans-Activators/metabolism Transfection Tumor Cells, Cultured
Schools and Departments: School of Life Sciences
Subjects: Q Science > QP Physiology
Depositing User: Gee Wheatley
Date Deposited: 03 May 2007
Last Modified: 30 Nov 2012 16:51
URI: http://sro.sussex.ac.uk/id/eprint/1058
Google Scholar:8 Citations
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