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.
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
J. Biol. Chem.
Date: Dec. 18, 2009
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