SMAD4 and neoplasm: It inhibits tumor growth in the early phase, but paradoxically, in the late phase it acts as a tumor promoter by enhancing EMT and promoting tumor cell invasion in primary carcinomas.12, 13 TGF-β binds to its receptors and activates Smad2 and Smad3, then phosphorylated SMAD2/3 partner with Smad4 to translocate into the nucleus where SMAD complexes control target gene transcription, including EMT- and motility-related genes.14