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.
Irie
Hanna Y
HY
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Pearline
Rachel V
RV
Grueneberg
Dorre
D
Hsia
Maximilian
M
Ravichandran
Preethi
P
Kothari
Nayantara
N
Natesan
Sridaran
S
Brugge
Joan S
JS
D015415:Biomarkers; D001940:Breast / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008648:Mesoderm / Q000201:enzymology / Q000378:metabolism*; D009024:Morphogenesis; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction
D015415:Biomarkers; D020033:Protein Isoforms; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases