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EGF regulates plasminogen activator inhibitor-1 (PAI-1) by a pathway involving c-Src, PKC, and sphingosine kinase 1 in glioblastoma cells

Barbara S. Paugh^*, Steven W. Paugh^*, Lauren Bryan^*, Dmitri Kapitonov^*, Katarzyna M. Wilczynska^*, Sunita M. Gopalan^*, Hanna Rokita, Sheldon Milstien, Sarah Spiegel^* and Tomasz Kordula^*,1

^* Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine/Massey Cancer Center, Richmond, Virginia, USA;

Faculty of Biotechnology, Jagiellonian University, Kraków, Poland; and

Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, Maryland, USA

¹Correspondence: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine/Massey Cancer Center, Richmond, VA 23298, USA. E-mail: tkordula{at}vcu.edu

Patients with gliomas expressing high levels of epidermal growth factor receptor (EGFR) and plasminogen activator inhibitor-1 (PAI-1) have a shorter overall survival prognosis. Moreover, EGF enhances PAI-1 expression in glioma cells. Although multiple known signaling cascades are activated by EGF in glioma cells, we show for the first time that EGF enhances expression of PAI-1 via sequential activation of c-Src, protein kinase C delta (PKC), and sphingosine kinase 1 (SphK1), the enzyme that produces sphingosine-1-phosphate. EGF induced rapid phosphorylation of c-Src and PKC and concomitant translocation of PKC as well as SphK1 to the plasma membrane. Down-regulation of PKC abolished EGF-induced SphK1 translocation and up-regulation of PAI-1 by EGF; whereas, down-regulation of PKC had no effect on the EGF-induced PAI-1 activation but enhanced its basal expression. Similarly, inhibition of c-Src activity by PP2 blocked both EGF-induced translocation of SphK1 and PKC to the plasma membrane and up-regulation of PAI-1 expression. Furthermore, SphK1 was indispensable for both EGF-induced c-Jun phosphorylation and PAI-1 expression. Collectively, our results provide a functional link between three critical downstream targets of EGF, c-Src, PKC, and SphK1 that have all been implicated in regulating motility and invasion of glioma cells.—Paugh, B. S., Paugh, S. W., Bryan, L., Kapitonov, D., Wilczynska, K. M., Gopalan, S. M., Rokita, H., Milstien, S., Spiegel, S., and Kordula, T. EGF regulates plasminogen activator inhibitor-1 by a pathway involving c-Src, PKC, and sphingosine kinase 1 in glioblastoma cells.

Key Words: glioma • invasiveness

This article has been cited by other articles:

				L. Bryan, B. S. Paugh, D. Kapitonov, K. M. Wilczynska, S. M. Alvarez, S. K. Singh, S. Milstien, S. Spiegel, and T. Kordula Sphingosine-1-Phosphate and Interleukin-1 Independently Regulate Plasminogen Activator Inhibitor-1 and Urokinase-Type Plasminogen Activator Receptor Expression in Glioblastoma Cells: Implications for Invasiveness Mol. Cancer Res., September 1, 2008; 6(9): 1469 - 1477. [Abstract] [Full Text] [PDF]