To test this hypothesis, we constructed a series of Smad4 mutants harboring 3 point mutations in the MH1 or MH2 domain that are commonly found in human cancers (Fig. 1B).4 Two of these, Pro130Ser and Asn351His (referred to herein as Smad4m130 and Smad4m351), had been reported to be rapidly degraded as a consequence of increased binding to β-TrCP.25 On the other hand, binding between Smad4 Ile383Lys (Smad4m383) and β-TrCP was not found to be significantly enhanced,25 and was used as a control. The gene discussed is SMAD4; the disease is cancer.