Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

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

RESEARCH ARTICLES

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).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Angiopoietin-2 Secretion by Endothelial Cell Exosomes: REGULATION BY THE PHOSPHATIDYLINOSITOL 3-KINASE (PI3K)/Akt/ENDOTHELIAL NITRIC OXIDE SYNTHASE (eNOS) AND SYNDECAN-4/SYNTENIN PATHWAYS.
R. Ju, Z. W. Zhuang, J. Zhang, A. A. Lanahan, T. Kyriakides, W. C. Sessa, and M. Simons (2014)
J. Biol. Chem. 289, 510-519
   Abstract »    Full Text »    PDF »
eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases.
A. Di Lorenzo, M. I. Lin, T. Murata, S. Landskroner-Eiger, M. Schleicher, M. Kothiya, Y. Iwakiri, J. Yu, P. L. Huang, and W. C. Sessa (2013)
J. Cell Sci. 126, 5541-5552
   Abstract »    Full Text »    PDF »
C-Reactive Protein Causes Insulin Resistance in Mice Through Fc{gamma} Receptor IIB-Mediated Inhibition of Skeletal Muscle Glucose Delivery.
K. Tanigaki, W. Vongpatanasin, J. A. Barrera, D. N. Atochin, P. L. Huang, E. Bonvini, P. W. Shaul, and C. Mineo (2013)
Diabetes 62, 721-731
   Abstract »    Full Text »    PDF »
Cavin-3 dictates the balance between ERK and Akt signaling.
V. J. Hernandez, J. Weng, P. Ly, S. Pompey, H. Dong, L. Mishra, M. Schwarz, R. G. Anderson, and P. Michaely (2013)
eLife Sci 2, e00905
   Abstract »    Full Text »    PDF »
Novel Role of the IGF-1 Receptor in Endothelial Function and Repair: Studies in Endothelium-Targeted IGF-1 Receptor Transgenic Mice.
H. Imrie, H. Viswambharan, P. Sukumar, A. Abbas, R. M. Cubbon, N. Yuldasheva, M. Gage, J. Smith, S. Galloway, A. Skromna, et al. (2012)
Diabetes 61, 2359-2368
   Abstract »    Full Text »    PDF »
Nitric oxide synthases: regulation and function.
U. Forstermann and W. C. Sessa (2012)
Eur. Heart J. 33, 829-837
   Abstract »    Full Text »    PDF »
Changing standard chow diet promotes vascular NOS dysfunction in Dahl S rats.
F. T. Spradley, D. H. Ho, K.-T. Kang, D. M. Pollock, and J. S. Pollock (2012)
Am J Physiol Regulatory Integrative Comp Physiol 302, R150-R158
   Abstract »    Full Text »    PDF »
Endothelial nitric oxide synthase controls the expression of the angiogenesis inhibitor thrombospondin 2.
S. MacLauchlan, J. Yu, M. Parrish, T. A. Asoulin, M. Schleicher, M. M. Krady, J. Zeng, P. L. Huang, W. C. Sessa, and T. R. Kyriakides (2011)
PNAS 108, E1137-E1145
   Abstract »    Full Text »    PDF »
Priming of hypoxia-inducible factor by neuronal nitric oxide synthase is essential for adaptive responses to severe anemia.
A. K. Y. Tsui, P. A. Marsden, C. D. Mazer, S. L. Adamson, R. M. Henkelman, J. J. D. Ho, D. F. Wilson, S. P. Heximer, K. A. Connelly, S.-S. Bolz, et al. (2011)
PNAS 108, 17544-17549
   Abstract »    Full Text »    PDF »
Bone Morphogenetic Protein Receptor II Is a Novel Mediator of Endothelial Nitric-oxide Synthase Activation.
A. Gangopahyay, M. Oran, E. M. Bauer, J. W. Wertz, S. A. Comhair, S. C. Erzurum, and P. M. Bauer (2011)
J. Biol. Chem. 286, 33134-33140
   Abstract »    Full Text »    PDF »
The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin Sensitivity in the Endothelium.
A. Abbas, H. Imrie, H. Viswambharan, P. Sukumar, A. Rajwani, R. M. Cubbon, M. Gage, J. Smith, S. Galloway, N. Yuldeshava, et al. (2011)
Diabetes 60, 2169-2178
   Abstract »    Full Text »    PDF »
Dimethylarginine Dimethylaminohydrolase 1 Modulates Endothelial Cell Growth Through Nitric Oxide and Akt.
P. Zhang, X. Hu, X. Xu, Y. Chen, and R. J. Bache (2011)
Arterioscler Thromb Vasc Biol 31, 890-897
   Abstract »    Full Text »    PDF »
HDAC5: going with the flow.
P. Huang (2010)
Blood 115, 2728-2729
   Full Text »    PDF »
Time Is of the Essence: Vascular Implications of the Circadian Clock.
R. D. Rudic (2009)
Circulation 120, 1714-1721
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882