Phosphorylation by Akt disables the anti-oncogenic activity of YB-1.
The Y box-binding protein 1 (YB-1) is a DNA/RNA-binding protein that regulates mRNA transcription and translation. It is a major component of free messenger ribonucleoprotein particles and, at higher concentrations, blocks protein synthesis. In chicken embryo fibroblasts, overexpression of YB-1 confers a specific resistance to oncogenic cellular transformation by phosphoinositide 3-kinase (PI3K) or Akt/PKB. Recent studies have identified YB-1 as a direct substrate of Akt. The functional significance of Akt-mediated phosphorylation remains largely unknown. We generated YB-1 mutants in the Akt phosphorylation consensus sequence to explore the effect of phosphorylated YB-1 in PI3K-induced transformation. In contrast to wild-type YB-1, the phosphomimetic S99E mutant no longer interferes with cellular transformation. This mutant has reduced affinity for the cap of mRNAs and fails to inhibit cap-dependent translation. The data suggest that phosphorylation by Akt disables the inhibitory activity of YB-1 and thereby enhances the translation of transcripts that are necessary for oncogenesis. Overexpression of wild-type YB-1 overrides inactivation by Akt and maintains inhibition of protein synthesis and resistance to transformation.
Bader
A G
AG
Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA 78744, USA.
Vogt
P K
PK
D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002642:Chick Embryo; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D051840:Y-Box-Binding Protein 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt