The Tumor Suppressor Smad4/DPC4 Is Regulated by Phosphorylations that Integrate FGF, Wnt, and TGF-β Signaling

• The tumor suppressor Smad4 is regulated by FGF/MAPK and Wnt/GSK3 phosphorylations
• Sequential phosphorylations control both Smad4 activity and degradation by β-TrCP
• In the presence of FGF, Wnt potentiates TGF-β at low physiological concentrations
• This mechanism controls germ layer and organizer specification in Xenopus

SummarySmad4 is a major tumor suppressor currently thought to function constitutively in the transforming growth factor β (TGF-β)-signaling pathway. Here, we report that Smad4 activity is directly regulated by the Wnt and fibroblast growth factor (FGF) pathways through GSK3 and mitogen-activated protein kinase (MAPK) phosphorylation sites. FGF activates MAPK, which primes three sequential GSK3 phosphorylations that generate a Wnt-regulated phosphodegron bound by the ubiquitin E3 ligase β-TrCP. In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region. When MAPK is not activated, the Wnt and TGF-β signaling pathways remain insulated from each other. In Xenopus embryos, these Smad4 phosphorylations regulate germ-layer specification and Spemann organizer formation. The results show that three major signaling pathways critical in development and cancer are integrated at the level of Smad4.

Graphical AbstractFigure optionsDownload as PowerPoint slide