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Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates.

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.

SUBMITTER: Lee MY

PROVIDER: S-EPMC4156707 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates.

Lee Monica Y MY Luciano Amelia K AK Ackah Eric E Rodriguez-Vita Juan J Bancroft Tara A TA Eichmann Anne A Simons Michael M Kyriakides Themis R TR Morales-Ruiz Manuel M Sessa William C WC

Proceedings of the National Academy of Sciences of the United States of America 20140818 35

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 phosphoryla ...[more]

PMID: 25136137

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Dataset Information

Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates.

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Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates.

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