The Akt1-eNOS axis illustrates the specificity of kinase-substrate relationships in vivo

Michael Schleicher, Jun Yu, Takahisa Murata, Berhad Derakhshan, Dimitriy Atochin, Li Qian, Satoshi Kashiwagi, Annarita Di Lorenzo, Kenneth D. Harrison, Paul L. Huang, William C. Sessa

Research output: Contribution to journalArticle

56 Citations (Scopus)

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 1α (HIF-1α) and increased production of HIF-1α-responsive genes in vivo and in vitro. Thus, Akt1 regulates angiogenesis largely through phosphorylation of eNOS and NO-dependent signaling.

Original languageEnglish
JournalScience Signaling
Volume2
Issue number82
DOIs
Publication statusPublished - 4 Aug 2009
Externally publishedYes

Fingerprint

Nitric Oxide Synthase Type III
Substrate Specificity
Phosphotransferases
Substrates
Serine
Hypoxia-Inducible Factor 1
Phosphorylation
Mutation
Aspartic Acid
Alanine
Substitution reactions
Stabilization
Genes
Phenotype
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Schleicher, M., Yu, J., Murata, T., Derakhshan, B., Atochin, D., Qian, L., ... Sessa, W. C. (2009). The Akt1-eNOS axis illustrates the specificity of kinase-substrate relationships in vivo. Science Signaling, 2(82). https://doi.org/10.1126/scisignal.2000343

The Akt1-eNOS axis illustrates the specificity of kinase-substrate relationships in vivo. / Schleicher, Michael; Yu, Jun; Murata, Takahisa; Derakhshan, Berhad; Atochin, Dimitriy; Qian, Li; Kashiwagi, Satoshi; Di Lorenzo, Annarita; Harrison, Kenneth D.; Huang, Paul L.; Sessa, William C.

In: Science Signaling, Vol. 2, No. 82, 04.08.2009.

Research output: Contribution to journalArticle

Schleicher, M, Yu, J, Murata, T, Derakhshan, B, Atochin, D, Qian, L, Kashiwagi, S, Di Lorenzo, A, Harrison, KD, Huang, PL & Sessa, WC 2009, 'The Akt1-eNOS axis illustrates the specificity of kinase-substrate relationships in vivo', Science Signaling, vol. 2, no. 82. https://doi.org/10.1126/scisignal.2000343
Schleicher, Michael ; Yu, Jun ; Murata, Takahisa ; Derakhshan, Berhad ; Atochin, Dimitriy ; Qian, Li ; Kashiwagi, Satoshi ; Di Lorenzo, Annarita ; Harrison, Kenneth D. ; Huang, Paul L. ; Sessa, William C. / The Akt1-eNOS axis illustrates the specificity of kinase-substrate relationships in vivo. In: Science Signaling. 2009 ; Vol. 2, No. 82.
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