Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells

mediated survival of endothelial cells. Am J Physiol Heart Circ Physiol 287: H1207–H1213, 2004. First published May 6, 2004; 10.1152/ajpheart.00020.2004.—Gas6 is a -carboxylated ligand for the receptor tyrosine kinase Axl. Gas6-Axl interactions can rescue endothelial cells from apoptosis, and this study examined the intra-cellular signaling mechanisms responsible for this phenomenon. Us-ing flow cytometry, we first confirmed that Gas6 can abrogate apop-tosis induced by serum starvation of primary cultures of human umbilical vein endothelial cells (HUVECs). This effect is mediated through phosphorylation of the serine-threonine kinase Akt, with maximal phosphorylation observed after 4 h of treatment with 100 ng/ml Gas6. Inhibition of Akt phosphorylation and abrogation of gas6-mediated survival of HUVECs by wortmannin implicated phos-phatidylinositol 3-kinase as the mediator of Akt phosphorylation. Dominant negative Akt constructs largely abrogated the protectiv