Smad4 is a critical transcription factor in the TGF-β pathway and loss of Smad4 is associated with malignant progression in prostate, colon, and pancreatic carcinomas.4,5 In the present work, we provide evidence that 2 Smad4 missense point mutations found in human cancers (Pro130Ser and Asn351His) increase Smad4 phosphorylation by the GSK3 kinase, thus triggering its degradation (Fig. 6). The gene discussed is SMAD4; the disease is exocrine pancreatic carcinoma.