Gas6 is a vitamin K-dependent protein containing gamma-carboxyglutamic acid (Gla) at its N-terminus and a receptor binding domain at its C-terminus. Gas6-Axl binding is necessary but not sufficient to support endothelial cell survival as decarboxylated gas6 inhibits the pro-survival function of gas6 by binding and inhibiting Axl, even though decarboxylated gas6 cannot support endothelial cell survival itself. It is hypothesized that interactions between the Gla domain of gas6 and phosphatidylserine (PS), though not required for gas6 binding to Axl, are necessary for gas6-Axl function. In support of this hypothesis are results showing that (1) two specific inhibitors of Gla-PS interactions, namely soluble PS and Annexin V, abrogate gas6-mediated endothelial cell survival and (2) Soluble PS inhibits Akt activation, a downstream intracellular event triggered by gas6-Axl binding. In conclusion, we propose a heretofore unknown function of Gla, where Gla-PS binding on the N-terminus of gas6 is necessary for a gas6 function mediated through its binding to Axl via its C-terminus. (C) 2008 Elsevier Inc. All rights reserved.