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

TLDR

Akt kinases are activated by growth factors and regulate diverse cellular functions. The study investigates isoform‑specific roles of Akt1 and Akt2 in growth‑factor–stimulated phenotypes of breast epithelial cells. Akt2 down‑regulation counteracts IGF‑IR–driven proliferation and survival, whereas Akt1 down‑regulation triggers EMT and migration through ERK activation; Akt2 also suppresses Akt1‑induced EMT and migration, underscoring distinct, isoform‑specific roles of Akt1 and Akt2 in growth‑factor–stimulated EMT and cell migration.

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.