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Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12865-70. doi: 10.1073/pnas.1408472111. Epub 2014 Aug 18.

Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520;
2
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520; Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
3
Institut d'Investigaciones Biomèdiques August Pi i Sunyer, Barcelona, Spain; and.
4
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520; Departments of Pathology and Biomedical Engineering and.
5
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520; Institut d'Investigaciones Biomèdiques August Pi i Sunyer, Barcelona, Spain; and Biochemistry and Molecular Genetics, Hospital Clinic of Barcelona, Networked Biomedical Research Center of Hepatic and Digestive Diseases (CIBERehd), 08036 Barcelona, Spain morales@clinic.ub.es william.sessa@yale.edu.
6
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520; Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; morales@clinic.ub.es william.sessa@yale.edu.

Abstract

The PI3K/Akt pathway is necessary for several key endothelial cell (EC) functions, including cell growth, migration, survival, and vascular tone. However, existing literature supports the idea that Akt can be either pro- or antiangiogenic, possibly due to compensation by multiple isoforms in the EC when a single isoform is deleted. Thus, biochemical, genetic, and proteomic studies were conducted to examine isoform-substrate specificity for Akt1 vs. Akt2. In vitro, Akt1 preferentially phosphorylates endothelial nitric oxide synthase (eNOS) and promotes NO release, whereas nonphysiological overexpression of Akt2 can bypass the loss of Akt1. Conditional deletion of Akt1 in the EC, in the absence or presence of Akt2, retards retinal angiogenesis, implying that Akt1 exerts a nonredundant function during physiological angiogenesis. Finally, proteomic analysis of Akt substrates isolated from Akt1- or Akt2-deficient ECs documents that phosphorylation of multiple Akt substrates regulating angiogenic signaling is reduced in Akt1-deficient, but not Akt2-deficient, ECs, including eNOS and Forkhead box proteins. Therefore, Akt1 promotes angiogenesis largely due to phosphorylation and regulation of important downstream effectors that promote aspects of angiogenic signaling.

KEYWORDS:

development; kinase; phosphoproteomics

PMID:
25136137
PMCID:
PMC4156707
DOI:
10.1073/pnas.1408472111
[Indexed for MEDLINE]
Free PMC Article

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