Title | The Akt1-eNOS axis illustrates the specificity of kinase-substrate relationships in vivo. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Schleicher M, Yu J, Murata T, Derakhshan B, Atochin D, Qian L, Kashiwagi S, Di Lorenzo A, Harrison KD, Huang PL, Sessa WC |
Journal | Sci Signal |
Volume | 2 |
Issue | 82 |
Pagination | ra41 |
Date Published | 2009 Aug 04 |
ISSN | 1937-9145 |
Keywords | Analysis of Variance, Animals, Blotting, Western, Crosses, Genetic, Fluorescent Antibody Technique, Indirect, Hypoxia-Inducible Factor 1, alpha Subunit, In Situ Nick-End Labeling, Mice, Mice, Knockout, Mutation, Neovascularization, Physiologic, Nitric Oxide Synthase Type III, Phosphorylation, Proto-Oncogene Proteins c-akt, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Substrate Specificity, Wound Healing |
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 1alpha (HIF-1alpha) and increased production of HIF-1alpha-responsive genes in vivo and in vitro. Thus, Akt1 regulates angiogenesis largely through phosphorylation of eNOS and NO-dependent signaling. |
DOI | 10.1126/scisignal.2000343 |
Alternate Journal | Sci Signal |
PubMed ID | 19654415 |
PubMed Central ID | PMC4750881 |
Grant List | P01 HL070295 / HL / NHLBI NIH HHS / United States R01 HL096670-02 / HL / NHLBI NIH HHS / United States R01 HL064793 / HL / NHLBI NIH HHS / United States R01 HL081190-07 / HL / NHLBI NIH HHS / United States N01HV28186 / HL / NHLBI NIH HHS / United States R01 HL064793-12 / HL / NHLBI NIH HHS / United States R37 HL061371-13 / HL / NHLBI NIH HHS / United States R37 HL061371 / HL / NHLBI NIH HHS / United States R01 HL057665 / HL / NHLBI NIH HHS / United States R01 HL096670 / HL / NHLBI NIH HHS / United States R01 HL081190 / HL / NHLBI NIH HHS / United States R01 NS033335 / NS / NINDS NIH HHS / United States R01 HL061371 / HL / NHLBI NIH HHS / United States |
Related Lab:
Related Faculty:
Annarita Di Lorenzo, Ph.D.