A Switch in Akt Isoforms Is Required for Notch-Induced Snail1 Expression and Protection from Cell Death

Notch activation in aortic endothelial cells (ECs) takes place at embryonic stages during cardiac valve formation and induces endothelial-to-mesenchymal transition (EndMT). Using aortic ECs, we show here that active Notch expression promotes EndMT, resulting in downregulation of vascular endothelial...

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Bibliographic Details
Published in:Molecular and cellular biology 2016-03, Vol.36 (6), p.923-940
Main Authors: Frías, Alex, Lambies, Guillem, Viñas-Castells, Rosa, Martínez-Guillamon, Catalina, Dave, Natàlia, García de Herreros, Antonio, Díaz, Víctor M.
Format: Article
Language:English
Subjects:
Animals
Aorta - cytology
beta Catenin - metabolism
Cell Death
Cell Line
Endothelial Cells - cytology
Endothelial Cells - metabolism
Epithelial-Mesenchymal Transition
Gene Expression Regulation
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 beta
HEK293 Cells
Humans
Mice
Oxidative Stress
Protein Isoforms - analysis
Protein Isoforms - genetics
Protein Isoforms - metabolism
Protein Stability
Proto-Oncogene Proteins c-akt - analysis
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Receptors, Notch - metabolism
Snail Family Transcription Factors
Swine
Transcription Factors - analysis
Transcription Factors - genetics
Transcription Factors - metabolism
Up-Regulation
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Summary:Notch activation in aortic endothelial cells (ECs) takes place at embryonic stages during cardiac valve formation and induces endothelial-to-mesenchymal transition (EndMT). Using aortic ECs, we show here that active Notch expression promotes EndMT, resulting in downregulation of vascular endothelial cadherin (VE-cadherin) and upregulation of mesenchymal genes such as those for fibronectin and Snail1/2. In these cells, transforming growth factor β1 exacerbates Notch effects by increasing Snail1 and fibronectin activation. When Notch-downstream pathways were analyzed, we detected an increase in glycogen synthase kinase 3β (GSK-3β) phosphorylation and inactivation that facilitates Snail1 nuclear retention and protein stabilization. However, the total activity of Akt was downregulated. The discrepancy between Akt activity and GSK-3β phosphorylation is explained by a Notch-induced switch in the Akt isoforms, whereby Akt1, the predominant isoform expressed in ECs, is decreased and Akt2 transcription is upregulated. Mechanistically, Akt2 induction requires the stimulation of the β-catenin/TCF4 transcriptional complex, which activates the Akt2 promoter. Active, phosphorylated Akt2 translocates to the nucleus in Notch-expressing cells, resulting in GSK-3β inactivation in this compartment. Akt2, but not Akt1, colocalizes in the nucleus with lamin B in the nuclear envelope. In addition to promoting GSK-3β inactivation, Notch downregulates Forkhead box O1 (FoxO1), another Akt2 nuclear substrate. Moreover, Notch protects ECs from oxidative stress-induced apoptosis through an Akt2- and Snail1-dependent mechanism.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.01074-15