Angiopoietin-2 Stimulation of Endothelial Cells Induces αvβ3 Integrin Internalization and Degradation

• Published in: The Journal of biological chemistry 2010-07, Vol.285 (31), p.23842-23849
• Main Authors: Thomas, Markus, Felcht, Moritz, Kruse, Karoline, Kretschmer, Stella, Deppermann, Carleen, Biesdorf, Andreas, Rohr, Karl, Benest, Andrew V., Fiedler, Ulrike, Augustin, Hellmut G.
• Format: Article
• Language: English
• Subjects: Angiopoietin; Cell Adhesion; Cell Biology; Cell Junctions; Endothelium; Integrin; Protein-tyrosine Kinase (Tyrosine Kinase); Tie; Vascular Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.097543

The angiopoietins (Ang-1 and Ang-2) have been identified as agonistic and antagonistic ligands of the endothelial receptor tyrosine kinase Tie2, respectively. Both ligands have been demonstrated to induce translocation of Tie2 to cell-cell junctions. However, only Ang-1 induces Tie2-dependent Akt activation and subsequent survival signaling and endothelial quiescence. Ang-2 interferes negatively with Ang-1/Tie2 signaling, thereby antagonizing the Ang-1/Tie2 axis. Here, we show that both Ang-1 and Ang-2 recruit β3 integrins to Tie2. This co-localization is most prominent in cell-cell junctions. However, only Ang-2 stimulation resulted in complex formation among Tie2, αvβ3 integrin, and focal adhesion kinase as evidenced by co-immunoprecipitation experiments. Focal adhesion kinase was phosphorylated in the FAT domain at Ser910 upon Ang-2 stimulation and the adaptor proteins p130Cas and talin dissociated from αvβ3 integrin. The αvβ3 integrin was internalized, ubiquitinylated, and gated toward lysosomes. Taken together, the experiments define Tie2/αvβ3 integrin association-induced integrin internalization and degradation as mechanistic consequences of endothelial Ang-2 stimulation.