MAP kinase and β-catenin signaling in HGF induced RPE migration

The morphologically and functionally polarized retinal pigment epithelium (RPE) has numerous functions including maintaining adjacent retinal photoreceptor cells and forming the outer blood-retinal barrier [1]. Differentiated RPE cells in the normal adult eye, however, retain the ability to migrate and proliferate in response to a wide range of pathological conditions [2], such as proliferative vitreoretinopathy (PVR; reviewed in [3,4]) and exudative age related macular degeneration [5]. Understanding the molecular mechanisms of RPE migration and proliferation is critical for development of therapeutic approaches for retinal diseases associated with proliferative RPE. Recent studies have suggested that several autocrine or paracrine loops involving cytokines, growth factors, and their receptors may be critical as pathological insults to RPE cells. These include platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis factor (TNF)-α, interleukin (IL)1 and 6, interferon-γ, transforming growth factor (TGF)-β, insulin-like growth factor (IGF), and hepatocyte growth factor (HGF) [6-9]. HGF, also known as scatter factor, may be particularly important due to its potent activity as a mitogen, motogen, and a pro-angiogenic factor that is involved in wound healing in many cell types (reviewed in [10]). Previous studies have suggested the role of HGF and its receptor, HGFR or c-met, in the migration and proliferation of cultured RPE cells or during epithelial-mesenchymal transition in PVR [8,11,12]. The HGF induced signaling pathways that lead to the epithelial-mesenchymal transition of RPE cells, however, have not been identified. Integrity of the epithelium is largely regulated by the tumor suppressor protein, adenomatous polyposis coli (APC) and associated proteins (reviewed in [13]). APC plays an important role in epithelial cell proliferation and migration [14]. APC functions by interacting with and down regulating βcatenin, a bi-functional molecule that either mediates cell adhesion under normal conditions or promotes cell proliferation and migration under pathological conditions. In the absence of pathological insults, cell adhesion is maintained by the cytoskeleton/cadherin/catenin complex. Any uncomplexed, cytosolic β-catenin is removed via the glycogen synthase kinase 3b (GSK3b)/APC/axin complex mediated serine phosphorylation and ubiquitin dependent protein degradation (reviewed © 2002 Molecular Vision