GAS6-induced signaling in human endothelial cells is mediated by FOXO1a

Authors

  • J. G. GANOPOLSKY,

    1. The Lady Davis Institute, Sir Mortimer Davis Jewish General Hospital, McGill University, Montreal, QC, Canada
    Search for more papers by this author
  • Md. R. ABID,

    1. The Center for Vascular Biology Research, Department of Medicine and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    Search for more papers by this author
  • W. C. AIRD,

    1. The Center for Vascular Biology Research, Department of Medicine and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    Search for more papers by this author
  • M. D. BLOSTEIN

    1. The Lady Davis Institute, Sir Mortimer Davis Jewish General Hospital, McGill University, Montreal, QC, Canada
    Search for more papers by this author
    • 1

      M. D. Blostein is a clinical research scholar of the Fonds de la Recherche Scentifique du Quebec.


Mark D. Blostein, Jewish General Hospital, 3755 Cote Sainte-Catherine Road, Room E-156, Montreal, QC H3T 1E2, Canada.
Tel.: +1 514 340 8222 ext 3992; fax: +1 514 227 5290.
E-mail: mark.blostein@staff.mcgill.ca

Abstract

Summary. Background: Growth Arrest Specific gene product 6 (gas6) is a γ-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. Results and 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, p27kip1. Taken together, these findings suggest that gas6 protects endothelial cells from apoptosis by a mechanism that involves PI3K-Akt-dependent inactivation of FOXO1a.

Ancillary