SMAD4 and colorectal carcinoma: Furthermore, studies have shown that in CRC, a mutation of arginine at position 361 of SMAD4 (SMAD4 R361) not only disrupts the binding of SMAD4 to phosphorylated SMAD2/3, thereby hindering normal TGF-β signal transduction and weakening TGF-β’s growth-inhibitory and apoptosis-inducing functions, but also potentially enhances SMAD4 binding to Lef1 protein.