When the cornea is wounded, there is a dramatic conversion of quiescent stromal keratocytes, first into motile, secretory fibroblasts, and then into contraction-ready, actin-rich myofibroblasts in response to TGF-beta. Myofibroblasts promote wound closure but few, if any, remain in a successfully-healed wound. We are exploring the role of urokinase-type plasminogen activator (uPA) in these phenotype conversions. uPA is a serine protease that promotes extracellular matrix degradation, cell migration, growth factor release, and tissue invasion by cancer cells and leukocytes. I will test the hypothesis that corneal stroma cells use uPA to regulate corneal healing analogous to its activity in invasive cells. The paradigm is that uPA, activated by binding to its receptor; uPAR, generates localized plasmin from plasminogen, which in turn releases biologically-active FGF. FGF increases uPA secretion, generating more plasmin from plasminogen. When plasmin levels are significantly elevated, plasmin activity releases active TGF-beta, which inhibits uPA secretion, and stimulates secretion of a uPA inhibitor, PAI, thus turning off growth factor signaling. uPAR, in addition to binding uPA, associates with integrins and extracellular matrix proteins uPAR/integrin/matrix association may be required for coordinated migration and extracellular protease activity.
| Bernstein, Audrey M; Twining, Sally S; Warejcka, Debra J et al. (2007) Urokinase receptor cleavage: a crucial step in fibroblast-to-myofibroblast differentiation. Mol Biol Cell 18:2716-27 |
| Greenberg, Roseanne S; Bernstein, Audrey M; Benezra, Miriam et al. (2006) FAK-dependent regulation of myofibroblast differentiation. FASEB J 20:1006-8 |
| Taliana, Lavinia; Benezra, Miriam; Greenberg, Roseanne S et al. (2005) ZO-1: lamellipodial localization in a corneal fibroblast wound model. Invest Ophthalmol Vis Sci 46:96-103 |
| Bernstein, Audrey M; Greenberg, Roseanne S; Taliana, Lavinia et al. (2004) Urokinase anchors uPAR to the actin cytoskeleton. Invest Ophthalmol Vis Sci 45:2967-77 |
