Tie2 [where 'Tie' is an acronym from tyrosine kinase with Ig and EGF (epidermal growth factor) homology domains] is a receptor tyrosine kinase expressed predominantly on the surface of endothelial cells. Activated by its ligands, the angiopoietins, Tie2 initiates signalling pathways that modulate vascular stability and angiogenesis. Deletion of either the Tie2 or Ang1 (angiopoietin-1) gene in mice results in lethal vascular defects, signifying their importance in vascular development. The mechanism employed by the Tie2 signalling machinery to attenuate or cause receptor trafficking is not well defined. Stimulation of Tie2-expressing cells with Ang1 results in its ubiquitylation, suggesting that this may provide the necessary signal for receptor turnover. Using a candidate molecule approach, we demonstrate that Tie2 co-immunoprecipitates with c-Cbl in an Ang1-dependent manner and its ubiquitylation can be inhibited by the dominant-interfering molecule v-Cbl (a viral form of c-Cbl that contains only the tyrosine kinase-binding domain region). Inhibition of the Tie2-Cbl interaction by overexpression of v-Cbl blocks ligand-induced Tie2 internalization and degradation. In summary, our results illustrate that c-Cbl interacts with the Tie2 signalling complex in a stimulation-dependent manner, and that this interaction is required for Tie2 ubiquitylation, internalization and degradation.