XB-ART-49622Cell Rep October 23, 2014; 9 (2): 688-700.
The tumor suppressor Smad4/DPC4 is regulated by phosphorylations that integrate FGF, Wnt, and TGF-β signaling.
Smad4 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.
PubMed ID: 25373906
Article link: Cell Rep
Species referenced: Xenopus
Genes referenced: gsk3b mapk1 smad4 smad4.2