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

Hanna Y. Irie, Rachel V. Pearline, Dorre Grueneberg, Maximilian Hsia, Preethi Ravichandran, Nayantara Kothari, Sridaran Natesan, Joan S. Brugge

Research output: Contribution to journalArticlepeer-review

509 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1023-1034
Number of pages12
JournalJournal of Cell Biology
Volume171
Issue number6
DOIs
StatePublished - 19 Dec 2005
Externally publishedYes

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