Functional analysis of keratins in embryonic and internal epithelia
Final Report Abstract
Intermediate filament proteins including vimentin have multiple roles in tissue homeostasis and protect cells against multiple forms of stress. The mechanisms by which they protect cells are not well understood. Vimentin is the major intermediate filament (IF) protein of mesenchymal cells and tissues and is co-expressed together with GFAP in glial cells and tissues. Here we show that vimentin regulates JAK-STAT signaling in cultured cells and in vivo by several mechanisms. Expression of a previously characterized Vim Delta C2B mutation caused upregulation of GFAP in lens epithelial and Müller glial cells of transgenic mice, accompanied by Tyr705 phosphorylation and nuclear translocation of STAT3. Cells transfected with Vim Delta C2B but not with wildtype vimentin showed robust activation of a SOCS3 reporter gene, suggesting that vimentin can activate STAT3 in the absence of extracellular ligands. In line, co-transfection of truncated vimentin mutants with STAT3 in fibroblasts revealed a direct interaction between coil2B of vimentin and STAT3 indicating that wildtype vimentin may sequester STAT3. Additional data suggest a role of vimentin in the turnover of STAT3. Thus, our data provide the first example for regulation of JAK-STAT signaling through a cytoskeletal protein.
