Figure 3.

Effects of SMAD4 loss and potential therapeutic strategies in SMAD4 signaling. In normal cells, SMAD4 acts as an intracellular mediator of TGFβ. In SMAD4-null cells, loss of SMAD4 leads to upregulation of the cell cycle and phosphoglycerate kinase 1 (PGK1), leading to tumor promotion. Therapies based on SMAD4 can be direct by targeting SMAD4 miRNA regulators to modulate SMAD4 or indirect by targeting a downstream component. SMAD4 loss leads to the enhanced efficacy of agents modulating the cell cycle, whereby SMAD4 as a biomarker could be useful to stratify therapies.