TGF-beta2 inhibits AKT activation and FGF-2-induced corneal endothelial cell proliferation

Exp Cell Res. 2006 Nov 1;312(18):3631-40. doi: 10.1016/j.yexcr.2006.08.004. Epub 2006 Aug 10.


The corneal endothelial cells form a boundary layer between anterior chamber and cornea. This single cell layer is important to maintain cornea transparency by eliciting net fluid transport into the anterior chamber. Injuries of the corneal endothelial layer in humans lead to corneal swelling and translucence. This hindrance is thought to be due to limited proliferative capacity of the endothelial layer. Fibroblast growth factor 2 (FGF-2) and transforming growth factor-beta 2 (TGF-beta2) are both found in aqueous humor, and these two cytokines promote and inhibit cell growth, respectively. The intracellular signaling mechanisms by which TGF-beta2 suppresses the mitogenic response to FGF-2, however, remain unclear. We have addressed this question by investigating potential crosstalk between FGF-2-induced and TGF-beta2-regulated intracellular signaling events in cultured bovine corneal endothelial (BCE) cells. We found that TGF-beta2 and FGF-2 oppositely affect BCE cell proliferation and TGF-beta2 can override the stimulating effects of FGF-2 by increasing COX-2 expression in these cells. Consistent with these findings, overexpression of COX-2 significantly reduced FGF-2-induced cell proliferation whereas a COX-2 specific inhibitor NS398 reversed the effect of TGF-beta2 on FGF-2-induced cell proliferation. The COX-2 product prostaglandin E2 (PGE-2) blocks FGF-2-induced cell proliferation. Whereas FGF-2 stimulates cell proliferation by activating the AKT pathway, TGF-beta2 and PGE-2 both inhibit this pathway. In accordance with the effect of PGE-2, cAMP also inhibits FGF-2-induced AKT activation. These findings suggest that the mitogenic response to FGF-2 in vivo in the corneal endothelial layer may be inhibited by TGF-beta2-induced suppression of the PI3-kinase/AKT signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Cell Cycle
  • Cell Line
  • Cell Proliferation / drug effects*
  • Cornea / cytology*
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / metabolism
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / metabolism
  • Dinoprostone / metabolism
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / physiology*
  • Enzyme Activation
  • Fibroblast Growth Factor 2 / pharmacology*
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • Signal Transduction / physiology
  • Transforming Growth Factor beta2 / pharmacology*


  • Cyclooxygenase 2 Inhibitors
  • Transforming Growth Factor beta2
  • Fibroblast Growth Factor 2
  • Cyclic AMP
  • Cyclooxygenase 2
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Dinoprostone