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

By H. Irie, R. Pearline, D. Grueneberg, Max Hsia, Preethi Ravichandran, N. Kothari, S. Natesan, J. Brugge. Journal of Cell Biology, 2005

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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.

Subfields: Hematology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e3908722c7c4023e66e8bf59f46611adab1e52d3

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In Hematology

Mina J. Bissell

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Citations in the corpus

PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. (2007, background): “Furthermore, recent reports reveal that Akt1 activation suppresses cell migration and invasion whereas Akt2 promotes invasion, particularly relevant in metastasis (Irie et al., 2005; Yoeli-Lerner et al., 2005).”
Targeting PI3K signalling in cancer: opportunities, challenges and limitations (2009, background): “Furthermore, studies in both mammary epithelial cell lines and in genetically engineered mouse breast cancer models suggest that AKT2 promotes cellular invasiveness and mesenchymal characteristics, whereas AKT1 promotes cellular survival and growt”
NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2 (2007, background): “A recent study has revealed a complex role for AKT isoforms in the EMT of MCF10A cells (Irie et al., 2005).”
Signaling mechanisms of the epithelial-mesenchymal transition (2014, background): “Silencing Akt2 using RNA interference is correlated with loss of EMT phenotype and increased expression of E-cadherin (115).”
AKT/PKB signaling: navigating downstream. (2007, unknown): “Strikingly, activation of Akt1 has been found to decrease mammary epithelial cell migration, and Akt1 prevents an epithelial-to-mesenchymal transition that resembles events required for metastasis (Irie et al., 2005; Yoeli-Lerner et al., 2005).”
The morphologies of breast cancer cell lines in three‐dimensional assays correlate with their profiles of gene expression (2007, background): “…the effects of the manipulation on the ability of these cells to execute acinar morphogenesis (Debnath et al., 2002, 2003; Gunawardane et al., 2005; Irie et al., 2005; Isakoff et al., 2005; Muthuswamy et al., 2001; Overholtzer et al., 2006; Reginato et al., 2003; Wrobel et al., 2004; Zhan et al.,…”
V600EBRAF is associated with disabled feedback inhibition of RAF–MEK signaling and elevated transcriptional output of the pathway (2009, background): “The data do not rule out that ERK signaling plays other roles in the biology of these tumors that are mediated by direct phosphorylation of substrates or modest increases in transcriptional output, including effects on invasion and angiogenesis (30, 31).”
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways (2017, background): “In terms of cancer, some studies have found that AKT2 may be the primary AKT for mediating PI3K-mediated metastatic processes [260,261], whereas others have concluded AKT1 to be as important [262–264].”