Hum. Reprod. Advance Access originally published online on May 16, 2008
Human Reproduction 2008 23(8):1733-1741; doi:10.1093/humrep/den178
Epidermal growth factor-stimulated extravillous cytotrophoblast motility is mediated by the activation of PI3-K, Akt and both p38 and p42/44 mitogen-activated protein kinases
1 Department of Microbiology and Immunology, Tulane University Health Sciences Center, New Orleans, LA, USA 2 Baylor College of Medicine, Department of Molecular and Cellular Biology, Houston, TX 77030, USA 3 Division of Basic Medical Sciences, St George's University of London, Cranmer Terrace, London SW17 0RE, UK 4 Mycobacterial Research National Institute for Medical Research, London NW7 1AA, UK
5 Correspondence address. Tel: +44-20-8725-5851; Fax: +44-20-8725-2992; E-mail: g.whitley{at}sgul.ac.uk
BACKGROUND: Trophoblast invasion is a temporally and spatially regulated scheme of events that can dictate pregnancy outcome. Evidence suggests that the potent mitogen epidermal growth factor (EGF) regulates cytotrophoblast (CTB) differentiation and invasion during early pregnancy.
METHODS AND RESULTS: In the present study, the first trimester extravillous CTB cell line SGHPL-4 was used to investigate the signalling pathways involved in the motile component of EGF-mediated CTB migration/invasion. EGF induced the phosphorylation of the phosphatidylinositol 3-kinase (PI3-K)-dependent proteins, Akt and GSK-3β as well as both p42/44 MAPK and p38 mitogen-activated protein kinases (MAPK). EGF-stimulated motility was significantly reduced following the inhibition of PI3-K (P < 0.001), Akt (P < 0.01) and both p42/44 MAPK (P < 0.001) and p38 MAPKs (P < 0.001) but not the inhibition of GSK-3β. Further analysis indicated that the p38 MAPK inhibitor SB 203580 inhibited EGF-stimulated phosphorylation of Akt on serine 473, which may be responsible for the effect SB 203580 has on CTB motility. Although Akt activation leads to GSK-3β phosphorylation and the subsequent expression of β-catenin, activation of this pathway by 1-azakenpaullone was insufficient to stimulate the motile phenotype.
CONCLUSION: We demonstrate a role for PI3-K, p42/44 MAPK and p38 MAPK in the stimulation of CTB cell motility by EGF, however activation of β-catenin alone was insufficient to stimulate cell motility.
Key words: epidermal growth factor/extravillous cytotrophoblast/motility/PI3-K/p38 mitogen-activated protein kinases
Submitted on January 2, 2007; resubmitted on February 11, 2008; accepted on March 20, 2008.
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