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Negative regulation of urokinase-type plasminogen activator production through FGF-2-mediated activation of phosphoinositide 3-kinase

Oncogene volume 21, pages 7027–7033 (2002)Cite this article

Abstract

Activation of phosphoinositide 3-kinase (PI3-kinase) is involved in many cellular responses. FGF-2 is one of the potent inducers of urokinase-type plasminogen activator (uPA) production in endothelial cells. However, little is known about the molecular mechanisms underlying FGF-2-mediated uPA production. Here we examined the signal transduction pathways involved in the regulation of uPA production by FGF-2-treatment. FGF-2 potently upregulated uPA production in murine brain capillary endothelial cells (IBE cells), as well as porcine aortic endothelial (PAE) cells and L6 myoblasts ectopically expressing FGFR1. PI3-kinase inhibitors, wortmannin and LY294002, both enhanced FGF-2-dependent uPA production by these cells. Stable expression of activated mutant p110α catalytic subunit of PI3-kinase into IBE cells decreased FGF-2-mediated uPA production, suggesting that PI3-kinase exhibited the negative regulatory effect on uPA production. No increase in FGF-2-induced PI3-kinase activity was observed in proteins immunoprecipitated by anti-phosphotyrosine antibody. Although stable expression of deleted mutant p85α regulatory subunit, which lacks association with p110 catalytic subunit, in IBE cells showed no dominant negative effect, transient expression of dominant negative Ras inhibited FGF-2-mediated PI3-kinase activation. These results suggest that only activated Ras contributed the FGF-2-mediated PI3-kinase activation. In cells stably expressing mutant p85α subunit, FGF-2 efficiently induced uPA production. Taken together, activation of PI3-kinase by FGF-2 is Ras-dependent and results in down-regulation of uPA production.

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Acknowledgements

We are grateful to Dr Carl-Henrik Heldin for the kind gifts of L6 myoblasts and PAE cells. We also acknowledge Drs Wataru Ogawa and Masato Kasuga for their kind gifts of plasmids encoding myristylated p110α catalytic subunit of bovine PI3-kinase and deleted mutant p85α regulatory subunit of bovine PI3-kinase. We also thank Dr Hiroshi Kikuchi for TFL-5 and -8 liposomes. The excellent outstanding help of Mr Takumi Shimogama and Ms Miki Yoshimoto in our laboratory, and members of the Nagasaki University Radioisotope Center is greatly appreciated. This work was partly supported by the Grant-in-Aid for Japan Society for the Promotion of Science.

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  1. Department of Urology, Nagasaki University School of Medicine, Nagasaki, Japan

    Yasushi Mochizuki, Satoshi Tsuda, Hiroshi Kanetake & Shigeru Kanda

  2. Department of Molecular Microbiology and Immunology, Division of Endothelial Cell Biology, Nagasaki University Graduate School of Medicine, Nagasaki, Japan

    Shigeru Kanda

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  1. Yasushi Mochizuki
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Correspondence to Shigeru Kanda.

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Mochizuki, Y., Tsuda, S., Kanetake, H. et al. Negative regulation of urokinase-type plasminogen activator production through FGF-2-mediated activation of phosphoinositide 3-kinase. Oncogene 21, 7027–7033 (2002). https://doi.org/10.1038/sj.onc.1205736

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