Investigation of the roles of Smad linker region phosphoryulation in epithelial-mesenchymal transition and tissue fibrosis.

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In cultures of retinal pigment epithelial cell line, ARPE-19 and mouse lens epithelial cell line, a-TN4, TGFbeta1 addition activates phosphorylation of Smad2/3 C-terminal and middle rinker region along with epithelial-mesenchymal transition (EMT). Phorphorylation of Smad2/3 middle lilnker was observed even under TGFbeta1-minus condition and seemed to be attenuated with inhibitors of MAPKs. Immunohistochemistry of human samples showed that EMT-lens cells exhibited phosphorylation of Smad3 middle renker region more prominently as compared with its C-terminus phosphrylation. C-terminus phosphorylation was not observed in smooth muscle action-positive cells. Rat lens injury experiments suggested that invlovement of JNK and p38 in Smad middle linker region phosphorylation. EMT-related gene expression was overall detecterd in mosue proliferative vitreoretinopathy (PVR) model. Immunohistochemistry showed both C-terminus and middle linker region phosphorylations of Smad3. Adenoviral overexpression of dominant negative p38 seemed to suppress middle linker region phosphorylation of Smad3. Investigations on human samples and its animal model, as well as cell culture experiments, suggetsed involvement of Smad3 middle linker region phosphorylation in EMT-related fibrogenic ocular pathologies.