The tumor suppressor Smad4/DPC4 is regulated by phosphorylations that integrate FGF, Wnt, and TGF-β signaling

Cell Rep. 2014 Oct 23;9(2):688-700. doi: 10.1016/j.celrep.2014.09.020. Epub 2014 Oct 16.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Fibroblast Growth Factors / metabolism*
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Phosphorylation
  • Rats
  • Smad4 Protein / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • Wnt Signaling Pathway*
  • Xenopus
  • beta-Transducin Repeat-Containing Proteins / metabolism

Substances

  • Smad4 Protein
  • Transforming Growth Factor beta
  • beta-Transducin Repeat-Containing Proteins
  • Fibroblast Growth Factors
  • Glycogen Synthase Kinase 3