We previously showed that Smad4 stability is controlled by Wnt-regulated GSK3 phosphorylations that generate a docking site for the ubiquitin E3 ligase β-TrCP.19 Others had observed that point mutations commonly found in colorectal and pancreatic cancers enhance the interaction between Smad4 and β-TrCP.25 Our discovery that the binding of Smad4 to β-TrCP requires GSK3 phosphorylation suggested that Smad4 containing point mutations may have an increased susceptibility to GSK3 phosphorylation. This evidence concerns the gene SMAD4 and familial pancreatic carcinoma.