SMAD4 and neoplasm: 33,34 Many tumors have mutations that activate Ras/Erk and Wnt signaling, causing mitogenic effects that will be counteracted by the increased activity of Smad4 and explaining the barrier effect of this key transcription factor during tumor progression.5,19 The ability to reverse Smad4 loss-of-function caused by specific point mutations using pharmacological agents may provide new therapeutic avenues.