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Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition.

The Akt family of kinases are activated by growth factors and regulate pleiotropic cellular activities. In this study, we provide evidence for isoform-specific positive and negative roles for Akt1 and -2 in regulating growth factor-stimulated phenotypes in breast epithelial cells. Insulin-like growth factor-I receptor (IGF-IR) hyperstimulation induced hyperproliferation and antiapoptotic activities that were reversed by Akt2 down-regulation. In contrast, Akt1 down-regulation in IGF-IR-stimulated cells promoted dramatic neomorphic effects characteristic of an epithelial-mesenchymal transition (EMT) and enhanced cell migration induced by IGF-I or EGF stimulation. The phenotypic effects of Akt1 down-regulation were accompanied by enhanced extracellular signal-related kinase (ERK) activation, which contributed to the induction of migration and EMT. Interestingly, down-regulation of Akt2 suppressed the EMT-like morphological conversion induced by Akt1 down-regulation in IGF-IR-overexpressing cells and inhibited migration in EGF-stimulated cells. These results highlight the distinct functions of Akt isoforms in regulating growth factor-stimulated EMT and cell migration, as well as the importance of Akt1 in cross-regulating the ERK signaling pathway.

Pubmed ID: 16365168

Authors

  • Irie HY
  • Pearline RV
  • Grueneberg D
  • Hsia M
  • Ravichandran P
  • Kothari N
  • Natesan S
  • Brugge JS

Journal

The Journal of cell biology

Publication Data

December 19, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: CA105134
  • Agency: NCI NIH HHS, Id: CA80111

Mesh Terms

  • Biological Markers
  • Breast
  • Cell Line
  • Cell Movement
  • Epidermal Growth Factor
  • Epithelial Cells
  • Extracellular Signal-Regulated MAP Kinases
  • Female
  • Gene Expression Regulation
  • Humans
  • Insulin-Like Growth Factor I
  • Mesoderm
  • Morphogenesis
  • Protein Isoforms
  • Proto-Oncogene Proteins c-akt
  • Receptor, IGF Type 1
  • Signal Transduction