Tie2 is a receptor tyrosine kinase expressed predominantly in endothelial cells. A missense mutation in the intracellular domain of Tie2 resulting in an arginine to tryptophan substitution causes an inherited form of vascular dysmorphogenesis, venous malformation (VM). The signalling pathways activated by mutant Tie2 and responsible for formation and maintenance of the abnormal vessels in VM are not known. In this study, we have sought to define these pathways by identifying phosphoproteins interacting with mutant Tie2 expressed in endothelial cells. We find R849W Tie2 is constitutively active in endothelium and recruits and phosphorylates a 52 kDa protein. This protein is identified as p52 ShcA. We show endothelial cells expressing VM-mutant Tie2 are protected from cell death and expression of dominant-negative ShcA inhibits the anti-apoptotic activity of the mutant receptor. Suppression of this pro-survival signalling could be a therapeutic option for inducing regression of lesional vessels. (c) 2006 Elsevier Inc. All rights reserved.