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  • Original Paper
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Activation of Stat3 preassembled with platelet-derived growth factor β receptors requires Src kinase activity

Oncogene volume 19, pages 2075–2085 (2000)Cite this article

Abstract

Members of the STAT family of transcriptional regulators modulate the expression of a variety of gene products that promote cell proliferation, survival and transformation. Although initially identified as mediators of cytokine signaling, the STAT proteins are also activated by, and thus may contribute to the actions of, polypeptide growth factors. To define the mechanism by which these factors activate STATs, we examined the process of Stat3 activation in Balb/c-3T3 fibroblasts treated with platelet-derived growth factor (PDGF). As STATs are activated by tyrosine phosphorylation, and as PDGF receptors are ligand-activated tyrosine kinases, we considered the possibility that Stat3 interacts with and is phosphorylated by PDGF receptors. We find that Stat3 associates with PDGF β receptors in both the presence and, surprisingly, the absence of PDGF. Moreover, Stat3 was phosphorylated on tyrosine in PDGF β receptor immunoprecipitates of PDGF-treated but not untreated cells. Although required, receptor activation was insufficient for Stat3 activation. When added to cells in combination with a pharmacologic agent (PD180970) that specifically inhibits the activity of Src family tyrosine kinases, PDGF did not activate Stat3 as monitored by electrophoretic mobility shift assay. PD180970 did not affect MAPK activation by PDGF or the JAK-dependent activation of Stat3 by interleukin-6. The necessity of Src activity for Stat3 activation by PDGF was further evidenced by data showing the presence of Src in complexes containing both Stat3 and PDGF β receptors in PDGF-treated cells. These results suggest a novel mechanism of STAT activation in which inactive Stat3 pre-assembles with inactive PDGF receptors, and in response to ligand binding and in a manner dependent on Src kinase activity, is rapidly phosphorylated and activated. Additional data demonstrate that Src kinase activity is also required for PDGF stimulation of DNA synthesis in density-arrested cells.

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Acknowledgements

This work was supported by the Cortner-Couch Endowed Chair for Cancer Research and NIH Grants CA67360 (WJ Pledger) and CA55652 (R Jove). The authors thank Dr Nancy Olashaw for manuscript preparation, and acknowledge the helpful service of the Flow Cytometry and Molecular Imaging Core Laboratories at the Moffitt Cancer Center.

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Authors and Affiliations

  1. Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, 33612, Florida, FL, USA

    Yi-Zhe Wang, Walker Wharton, Roy Garcia, Richard Jove & W J Pledger

  2. Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, 33612, Florida, FL, USA

    Yi-Zhe Wang

  3. Department of Pathology, University of South Florida College of Medicine, Tampa, 33612, Florida, FL, USA

    Walker Wharton & Richard Jove

  4. Department of Biochemistry and Molecular Biology, University of South Florida College of Medicine, Tampa, 33612, Florida, FL, USA

    Richard Jove & W J Pledger

  5. Department of Medicinal Chemistry, Cancer Research, Parke-Davis Pharmaceutical Research, Ann Arbor, 48105, Michigan, MI, USA

    Alan Kraker

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Wang, YZ., Wharton, W., Garcia, R. et al. Activation of Stat3 preassembled with platelet-derived growth factor β receptors requires Src kinase activity. Oncogene 19, 2075–2085 (2000). https://doi.org/10.1038/sj.onc.1203548

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