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

doi:10.1083/jcb.200505087

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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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 andregulate pleiotropic cellular activities. In this study, weprovide evidence for isoform-specific positive and negativeroles for Akt1 and -2 in regulating growth factor–stimulatedphenotypes in breast epithelial cells. Insulin-like growth factor-Ireceptor (IGF-IR) hyperstimulation induced hyperproliferationand antiapoptotic activities that were reversed by Akt2 down-regulation.In contrast, Akt1 down-regulation in IGF-IR–stimulatedcells promoted dramatic neomorphic effects characteristic ofan epithelial–mesenchymal transition (EMT) and enhancedcell migration induced by IGF-I or EGF stimulation. The phenotypiceffects of Akt1 down-regulation were accompanied by enhancedextracellular signal–related kinase (ERK) activation,which contributed to the induction of migration and EMT. Interestingly,down-regulation of Akt2 suppressed the EMT-like morphologicalconversion induced by Akt1 down-regulation in IGF-IR–overexpressingcells and inhibited migration in EGF-stimulated cells. Theseresults highlight the distinct functions of Akt isoforms inregulating growth factor–stimulated EMT and cell migration,as well as the importance of Akt1 in cross-regulating the ERKsignaling pathway.

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

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

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