SMAD7

SMAD7 is the general inhibitory SMAD that terminates both TGF-β and BMP signaling. Located on chromosome 18q21 adjacent to SMAD2, SMAD7 is an immediate-early gene induced by these same pathways and by inflammatory stimuli such as NF-κB and shear stress, establishing negative feedback loops. Mechanistically, SMAD7 resides in the nucleus, translocates to activated type I receptors and recruits SMURF1/SMURF2 and the GADD34-PP1c phosphatase complex to dephosphorylate or ubiquitinate receptors, while also disrupting functional R-SMAD assembly and recruiting transcriptional corepressors. Functionally, SMAD7 constrains TGF-β-driven fibrosis, epithelial-mesenchymal transition and growth inhibition: in inflammatory bowel disease, mucosal SMAD7 is overexpressed, blocking TGF-β1-mediated suppression of inflammation, and mongersen, an oral SMAD7 antisense oligonucleotide, was developed for Crohn's disease. In cancer, SMAD7 can act as tumor suppressor (impairing TGF-β metastasis program) or promoter (restraining TGF-β cytostasis), whereas in liver and kidney fibrosis models SMAD7 gene transfer attenuates collagen deposition.