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The phosphatidylinositol 3-kinase/Akt pathway regulates transforming growth factor-{beta} signaling by destabilizing ski and inducing Smad7.

Ski is an oncoprotein that negatively regulates transforming growth factor (TGF)-beta signaling. It acts as a transcriptional co-repressor by binding to TGF-beta signaling molecules, Smads. Efficient TGF-beta signaling is facilitated by rapid proteasome-mediated degradation of Ski by TGF-beta. Here we report that Ski is phosphorylated by Akt/PKB kinase. Akt phosphorylates Ski on a highly conserved Akt motif at threonine 458 both in vitro and in vivo. The phosphorylation of Ski at threonine 458 is induced by Akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of Ski causes its destabilization and reduces Ski-mediated inhibition of expression of another negative regulator of TGF-beta, Smad7. Induction of Smad7 levels leads to inactivation of TGF-beta receptors and TGF-beta signaling cascade, as indicated by reduced induction of TGF-beta target p15. Therefore, Akt modulates TGF-beta signaling by temporarily adjusting the levels of two TGF-beta pathway negative regulators, Ski and Smad7. These novel findings demonstrate that Akt pathway activation directly impacts TGF-beta pathway.

Pubmed ID: 19875456


  • Band AM
  • Bj√∂rklund M
  • Laiho M


The Journal of biological chemistry

Publication Data

December 18, 2009

Associated Grants


Mesh Terms

  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Cercopithecus aethiops
  • DNA-Binding Proteins
  • Hepatocyte Growth Factor
  • Humans
  • Hypoglycemic Agents
  • Insulin
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Protein Stability
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Receptors, Transforming Growth Factor beta
  • Signal Transduction
  • Smad7 Protein
  • Transforming Growth Factor beta