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EGF regulates plasminogen activator inhibitor-1 (PAI-1) by a pathway involving c-Src, PKCdelta, 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.
Affiliation
  • Paugh BS; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine/Massey Cancer Center, Richmond, VA 23298, USA.
FASEB J ; 22(2): 455-65, 2008 Feb.
Article in En | MEDLINE | ID: mdl-17855624
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Proto-Oncogene Proteins pp60(c-src) / Plasminogen Activator Inhibitor 1 / Phosphotransferases (Alcohol Group Acceptor) / Glioblastoma / Epidermal Growth Factor / Protein Kinase C-delta Type of study: Prognostic_studies Limits: Humans Language: En Journal: FASEB J Journal subject: BIOLOGIA / FISIOLOGIA Year: 2008 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Proto-Oncogene Proteins pp60(c-src) / Plasminogen Activator Inhibitor 1 / Phosphotransferases (Alcohol Group Acceptor) / Glioblastoma / Epidermal Growth Factor / Protein Kinase C-delta Type of study: Prognostic_studies Limits: Humans Language: En Journal: FASEB J Journal subject: BIOLOGIA / FISIOLOGIA Year: 2008 Document type: Article Affiliation country: United States Country of publication: United States