Ligand binding to the extracellular domain of Tie2 results in receptor dimerization, autophosphorylation and docking of adaptors, and coupling to intracellular signalling pathways [47, [53] [54] [55] . Tie2 is shed from the EC and can be detected in soluble form in normal human serum and plasma; soluble Tie2 may be involved in ligand scavenging without signalling [56] . Tie2 shedding is both constitutive and induced; the latter can be controlled by VEGF via a pathway that is dependent on phosphoinositide-3 kinase (PI3K) and Akt [57] . Shed soluble Tie2 can scavenge Ang-1 and Ang-2 [56] . Tie1 does not act as a transmembrane kinase; rather, it regulates the binding of ligands to Tie2 and modulates its signalling [58] [59] [60] .