RT Journal Article
SR Electronic
T1 The Akt1-eNOS Axis Illustrates the Specificity of Kinase-Substrate Relationships in Vivo
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra41
OP ra41
DO 10.1126/scisignal.2000343
VO 2
IS 82
A1 Schleicher, Michael
A1 Yu, Jun
A1 Murata, Takahisa
A1 Derakhshan, Berhad
A1 Atochin, Dimitriy
A1 Qian, Li
A1 Kashiwagi, Satoshi
A1 Di Lorenzo, Annarita
A1 Harrison, Kenneth D.
A1 Huang, Paul L.
A1 Sessa, William C.
YR 2009
UL http://stke.sciencemag.org/content/2/82/ra41.abstract
AB 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.