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

• Published in: The FASEB journal Vol. 22; no. 2; pp. 455 - 465
• Main Authors: Paugh, Barbara S, Paugh, Steven W, Bryan, Lauren, Kapitonov, Dmitri, Wilczynska, Katarzyna M, Gopalan, Sunita M, Rokita, Hanna, Milstien, Sheldon, Spiegel, Sarah, Kordula, Tomasz
• Format: Journal Article
• Language: English
• Published: The Federation of American Societies for Experimental Biology 01.02.2008
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.07-8276com

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.