EGF regulates plasminogen activator inhibitor-1 (PAI-1) by a pathway involving c-Src, PKCδ, 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 1 Correspondence: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine/Massey Cancer Center, Richmond, VA 23298, USA. E-mail: tkordula@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 (PKCδ), and sphingosine kinase 1 (SphK1), the enzyme that produces sphingosine-1-phosphate. EGF induced rapid phosphorylation of c-Src and PKCδ and concomitant translocation of PKCδ as well as SphK1 to the plasma membrane. Down-regulation of PKCδ abolished EGF-induced SphK1 translocation and up-regulation of PAI-1 by EGF; whereas, down-regulation of PKCα 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 PKCδ 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, PKCδ, 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, PKCδ, and sphingosine kinase 1 in glioblastoma cells. Key Words: glioma • invasiveness
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EGF regulates plasminogen activator inhibitor-1 (PAI-1) by a pathway involving c-Src, PKCδ, and sphingosine kinase 1 in glioblastoma cells
Paugh, Barbara S.; Paugh, Steven W.; Bryan, Lauren; Kapitonov, Dmitri; Wilczynska, Katarzyna M.; Gopalan, Sunita M.; Rokita, Hanna; Milstien, Sheldon; Spiegel, Sarah; Kordula, Tomasz
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, Volume 22 (2): 455
Fed of American Socs for Experimental Biology – Feb 1, 2008
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