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

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...

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Bibliographic Details
Published in:The FASEB journal 2008-02, Vol.22 (2), p.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: Article
Language:English
Subjects:
Cell Line, Tumor
Epidermal Growth Factor - pharmacology
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
Glioblastoma - genetics
Glioblastoma - metabolism
Humans
NF-kappa B - metabolism
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Plasminogen Activator Inhibitor 1 - genetics
Plasminogen Activator Inhibitor 1 - metabolism
Protein Kinase C-alpha - genetics
Protein Kinase C-alpha - metabolism
Protein Kinase C-delta - genetics
Protein Kinase C-delta - metabolism
Proto-Oncogene Proteins pp60(c-src) - metabolism
Signal Transduction - drug effects
STAT Transcription Factors - metabolism
Transcription Factor AP-1 - metabolism
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Summary: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.
ISSN:1530-6860