SMAD3, also named as hMAD 3 or Mad3, is a 425 amino acid protein, which contains one MH1 domain and one MH2 domain. Phospho-SMAD3 (Ser423/425) is the dual-phosphorylated, active form of SMAD3 that results from TGF-β, activin or BMP receptor kinase signaling. Upon ligand binding, the type II receptor phosphorylates the type I receptor, which in turn phosphorylates SMAD3 at Ser423 and Ser425 within the SSXS motif. This creates a binding surface for SMAD4, forming the heterotrimeric transcription complex that translocates to the nucleus to regulate genes involved in cell cycle control, fibrosis, immune modulation and epithelial-mesenchymal transition (EMT).