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Published 19 December 2005. doi:10.1083/jcb.200505087
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 6, 1023-1034
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Article

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

Hanna Y. Irie1,2, Rachel V. Pearline1, Dorre Grueneberg3, Maximilian Hsia3, Preethi Ravichandran3, Nayantara Kothari3, Sridaran Natesan3, and Joan S. Brugge1

1 Department of Cell Biology, Harvard Medical School, Boston, MA 02115
2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
3 Sanofi-Aventis Pharmaceuticals, Cambridge Genomics Center, Cambridge, MA 02139

Correspondence to Joan S. Brugge: joan_brugge{at}hms.harvard.edu

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.

Dorre Gruneberg's present address is Dept. of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.

Abbreviations used in this paper: 3D, three-dimensional; EMT, epithelial–mesenchymal transition; ERK, extracellular signal–related kinase; GSK3, glycogen synthase kinase-3; IGF-IR, insulin-like growth factor-I receptor; PH, pleckstrin homology; PI 3-kinase, phosphatidyl-inositol 3' kinase; shRNA, short hairpin RNA.


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