The stromal tissue, made of extracellular matrix and mesenchymal cells, is vital for the functional design of all complex tissues. Fibroblasts are key components of stromal tissue and play a crucial role during organ development, wound repair, angiogenesis and fibrosis. We have previously reported the identification of a novel WD-domain protein, STRAP(1) that inhibits transforming growth factor-beta (TGF-beta) signaling and enhances tumorigenicity via TGF-beta-dependent and TGF-beta-independent mechanisms. Here, we report, for the first time, that deletion of STRAP from Mouse Embryonic Fibroblasts (MEFs) results in a loss of mesenchymal morphology. These cells lose their spindle shape and exhibit features of an epithelial morphology. Gene expression profiling has confirmed that deletion of STRAP affects expression of sets of genes important for diverse functions including cell-cell adhesion and cell polarization, and upregulates E-cadherin expression leading to the formation of adherens junctions, subsequent localization of beta-catenin to the cell membrane and downregulation of the mesenchymal markers like LEF1 (lymphoid enhancer-binding factor 1). Upregulation of WT1 (Wilms tumor homolog 1) in STRAP null MEFs plays a role in E-cadherin induction. Finally, stable expression of STRAP in these cells results in a loss of WT1 and E-cadherin expressions, and a reversal from epithelial to the mesenchymal morphology. Thus, these results provide a novel TGF-beta-independent function of STRAP and describe a mechanism for the role of STRAP in the maintenance of mesenchymal morphology.