Smads are critical mediators conveying signals from the TGF-β-superfamily members to the nucleus. Activated TGF-β type I receptor (TβRI) and c-Jun N-terminal kinase (JNK) differentially phosphorylate Smad3 to convert two distinctive phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Reversible shifting of Smad-dependent signaling between tumor suppression and oncogenesis in hyperactive Ras-expressing cells indicates that pSmad3C transmits a tumor-suppressive TGF-β signal in mature epithelial cells, while oncogenic activities such as cell proliferation and invasion are promoted by the pSmad3L pathway. Notably, pSmad3L-mediated signaling in activated mesenchymal cells promotes fibrosis by stimulating extracellular matrix deposition. As neoplasia progresses from normal epithelial cells through adenoma to cancer, the cells undergo transition from the tumor-suppressive pSmad3C pathway, which is characteristic of mature epithelial cells, to the JNK/pSmad3L pathway, which appears to favor the state of flux shown by the activated mesenchymal cells. Analysis of domain-specific phosphorylation states of Smad3 with the Abs should enhance understanding of TGF-β signaling in cancer and fibrosis, and help many researchers seek for new treatments of such diseases.
