PMID- 10469573
OWN - NLM
STAT- MEDLINE
DCOM- 19991101
LR  - 20190728
IS  - 0960-9822 (Print)
IS  - 0960-9822 (Linking)
VI  - 9
IP  - 15
DP  - 1999 Jul 29-Aug 12
TI  - The Akt kinase signals directly to endothelial nitric oxide synthase.
PG  - 845-8
AB  - Endothelial nitric oxide synthase (eNOS) is an important modulator of
      angiogenesis and vascular tone [1]. It is stimulated by treatment of endothelial 
      cells in a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent fashion by
      insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor
      (VEGF) [2] [3] and is activated by phosphorylation at Ser1177 in the sequence
      RIRTQS(1177)F (in the single-letter amino acid code) [4]. The protein kinase Akt 
      is an important downstream target of PI 3-kinase [5] [6], regulating
      VEGF-stimulated endothelial cell survival [7]. Akt phosphorylates substrates
      within a defined motif [8], which is present in the sequence surrounding Ser1177 
      in eNOS. Both Akt [5] [6] and eNOS [9] are localized to, and activated at, the
      plasma membrane. We found that purified Akt phosphorylated cardiac eNOS at
      Ser1177, resulting in activation of eNOS. Phosphorylation at this site was
      stimulated by treatment of bovine aortic endothelial cells (BAECs) with VEGF or
      IGF-1, and Akt was activated in parallel. Preincubation with wortmannin, an
      inhibitor of Akt signalling, reduced VEGF- or IGF-1-induced Akt activity and eNOS
      phosphorylation. Akt was detected in immunoprecipitates of eNOS from BAECs, and
      eNOS in immunoprecipitates of Akt, indicating that the two enzymes associate in
      vivo. It is thus apparent that Akt directly activates eNOS in endothelial cells. 
      These results strongly suggest that Akt has an important role in the regulation
      of normal angiogenesis and raise the possibility that the enhanced activity of
      this kinase that occurs in carcinomas may contribute to tumor vascularization and
      survival.
FAU - Michell, B J
AU  - Michell BJ
AD  - St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy,
      Victoria, 3065, Australia.
FAU - Griffiths, J E
AU  - Griffiths JE
FAU - Mitchelhill, K I
AU  - Mitchelhill KI
FAU - Rodriguez-Crespo, I
AU  - Rodriguez-Crespo I
FAU - Tiganis, T
AU  - Tiganis T
FAU - Bozinovski, S
AU  - Bozinovski S
FAU - de Montellano, P R
AU  - de Montellano PR
FAU - Kemp, B E
AU  - Kemp BE
FAU - Pearson, R B
AU  - Pearson RB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Curr Biol
JT  - Current biology : CB
JID - 9107782
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Lymphokines)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 1.14.13.39 (NOS3 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - Cattle
MH  - Cell Line
MH  - Cells, Cultured
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - Endothelial Growth Factors/pharmacology
MH  - Endothelium, Vascular/drug effects/metabolism
MH  - Humans
MH  - Insulin-Like Growth Factor I/pharmacology
MH  - Lymphokines/pharmacology
MH  - Molecular Sequence Data
MH  - Nitric Oxide Synthase/chemistry/genetics/*metabolism
MH  - Nitric Oxide Synthase Type III
MH  - Phosphorylation
MH  - Protein-Serine-Threonine Kinases/genetics/*metabolism
MH  - *Proto-Oncogene Proteins
MH  - Proto-Oncogene Proteins c-akt
MH  - Recombinant Fusion Proteins/genetics/metabolism
MH  - Signal Transduction
MH  - Transfection
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 1999/09/02 00:00
MHDA- 1999/09/02 00:01
CRDT- 1999/09/02 00:00
PHST- 1999/09/02 00:00 [pubmed]
PHST- 1999/09/02 00:01 [medline]
PHST- 1999/09/02 00:00 [entrez]
AID - S0960-9822(99)80371-6 [pii]
AID - 10.1016/s0960-9822(99)80371-6 [doi]
PST - ppublish
SO  - Curr Biol. 1999 Jul 29-Aug 12;9(15):845-8. doi: 10.1016/s0960-9822(99)80371-6.