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

Abstract

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 (PKCdelta), and sphingosine kinase 1 (SphK1), the enzyme that produces sphingosine-1-phosphate. EGF induced rapid phosphorylation of c-Src and PKCdelta and concomitant translocation of PKCdelta as well as SphK1 to the plasma membrane. Down-regulation of PKCdelta abolished EGF-induced SphK1 translocation and up-regulation of PAI-1 by EGF; whereas, down-regulation of PKCalpha 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 PKCdelta 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, PKCdelta, and SphK1 that have all been implicated in regulating motility and invasion of glioma cells.

Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer

“…The present in vitro data demonstrate that a IL-6 and PAI-1 co-expression in epithelial ovarian cancer C Alberti et al signaling cascade from ligand-stimulated EGFR/MEK/ ERK or EGFR/PI3K/AKT activates the transcriptional activity of NFkB with expression of IL-6 together with PAI-1. A similar signaling pathway has been experimentally demonstrated in glioblastoma cell lines (Paugh et al, 2008), and a positive correlation between PAI-1 and IL-6 gene expression has been observed in a metaanalysis carried out on publicly available data sets of gene expression of breast carcinoma (Sternlicht et al, 2006). Interestingly, very recently ErbB2 expression, another member of the ErbB family, was found to upregulate IL-6 production through the transcriptional activity of NFkB (Hartman et al, 2011).…”

Synergistic and Multidimensional Regulation of Plasminogen Activator Inhibitor Type 1 Expression by Transforming Growth Factor Type β and Epidermal Growth Factor

“…Consistent with this conclusion is our observation and that of others of the synergism between TGF␤ and growth factors that stimulate the MAPK pathway (44,45). Protein kinase C can also activate the MAPK pathway, and in glioma cells, PKC␦ is activated by EGF via Src (46). However, in this study, we found that inhibiting Src did not prevent synergism between EGF and TGF␤.…”

Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

“…EGF, just like HA, induces expression of PAI-1 by PKC delta in glioblastoma cells (Paugh et al, 2008). TNF-α regulates TGFβ-promoted epithelial mesenchymal transition (EMT) by inducing HA-CD44-moesin interaction (Takahashi et al, 2010), suggesting transactivation of TGFβRI by TNF-α.…”