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Sci. Signal., 4 August 2009
Vol. 2, Issue 82, p. ra41
[DOI: 10.1126/scisignal.2000343]

RESEARCH

The Akt1-eNOS Axis Illustrates the Specificity of Kinase-Substrate Relationships in Vivo

Michael Schleicher1, Jun Yu1, Takahisa Murata2, Berhad Derakhshan1, Dimitriy Atochin3, Li Qian3, Satoshi Kashiwagi3, Annarita Di Lorenzo1, Kenneth D. Harrison1, Paul L. Huang3*, and William C. Sessa1*

1 Department of Pharmacology and Vascular Biology and Therapeutics Program, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA.
2 Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
3 Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, MA 02129, USA.

Abstract: Akt1 is critical for many in vivo functions; however, the cell-specific substrates responsible remain to be defined. Here, we examine the importance of endothelial nitric oxide synthase (eNOS) as an Akt1 substrate by generating Akt1-deficient mice (Akt1–/– mice) carrying knock-in mutations (serine to aspartate or serine to alanine substitutions) of the critical Akt1 phosphorylation site on eNOS (serine 1176) that render the enzyme "constitutively active" or "less active." The eNOS mutations did not influence several phenotypes in Akt1–/– mice; however, the defective postnatal angiogenesis characteristic of Akt1–/– mice was rescued by crossing the Akt1–/– mice with mice carrying the constitutively active form of eNOS, but not by crossing with mice carrying the less active eNOS mutant. This genetic rescue resulted in the stabilization of hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) and increased production of HIF-1{alpha}–responsive genes in vivo and in vitro. Thus, Akt1 regulates angiogenesis largely through phosphorylation of eNOS and NO-dependent signaling.

* To whom correspondence should be addressed. E-mail: huangp{at}helix.mgh.harvard.edu (P.L.H.) and william.sessa{at}yale.edu (W.C.S.)

Citation: M. Schleicher, J. Yu, T. Murata, B. Derakhshan, D. Atochin, L. Qian, S. Kashiwagi, A. Di Lorenzo, K. D. Harrison, P. L. Huang, W. C. Sessa, The Akt1-eNOS Axis Illustrates the Specificity of Kinase-Substrate Relationships in Vivo. Sci. Signal. 2, ra41 (2009).

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