GAS6-induced signaling in human endothelial cells is mediated by FOXO1a.
BACKGROUND
Growth Arrest Specific gene product 6 (gas6) is a gamma-carboxylated protein that protects endothelial cells against apoptosis. Gas6 has previously been shown to induce phospatidyl-3-inositol-kinase (PI3K)/Akt signaling. Other studies have demonstrated a link between PI3K/Akt signaling and forkhead transcription factors in endothelial cells.


OBJECTIVE
To test the hypothesis that gas6 promotes cell survival via a forkhead-dependent pathway.


CONCLUSIONS
Treatment of serum-starved human umbilical vein endothelial cells (HUVECs) with gas6 induced time-dependent phosphorylation and nuclear exclusion of FOXO1a. This effect was suppressed by the PI3K inhibitor wortmannin, demonstrating that FOXO1a phosphorylation is PI3-kinase dependent. Transduction of HUVECs with a phosphorylation-resistant form of FOXO1a [triple mutant (TM)-FOXO1a] abrogated the pro-survival effect of gas6 on serum-starved endothelial cells. Finally, treatment of serum-starved HUVECs with gas6 resulted in a reduction of FOXO1a transcriptional activity and downregulation of the pro-apoptotic gene, p27(kip1). Taken together, these findings suggest that gas6 protects endothelial cells from apoptosis by a mechanism that involves PI3K-Akt-dependent inactivation of FOXO1a.
Ganopolsky
J G
JG
The Lady Davis Institute, Sir Mortimer Davis Jewish General Hospital, McGill University, Montreal, QC, Canada.
Abid
Md R
MR
Aird
W C
WC
Blostein
M D
MD
D021581:Active Transport, Cell Nucleus; D002470:Cell Survival; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007700:Kinetics; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D015398:Signal Transduction; D014158:Transcription, Genetic; D014471:Umbilical Veins / Q000166:cytology; D000099255:Growth Arrest-Specific Protein 6
D050760:Cyclin-Dependent Kinase Inhibitor p27; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000099255:Growth Arrest-Specific Protein 6; C085126:FOXO1 protein, human