Angiopoietin-2 stimulation of endothelial cells induces alphavbeta3 integrin internalization and degradation.
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 beta3 integrins to Tie2. This co-localization is most prominent in cell-cell junctions. However, only Ang-2 stimulation resulted in complex formation among Tie2, alphavbeta3 integrin, and focal adhesion kinase as evidenced by co-immunoprecipitation experiments. Focal adhesion kinase was phosphorylated in the FAT domain at Ser(910) upon Ang-2 stimulation and the adaptor proteins p130Cas and talin dissociated from alphavbeta3 integrin. The alphavbeta3 integrin was internalized, ubiquitinylated, and gated toward lysosomes. Taken together, the experiments define Tie2/alphavbeta3 integrin association-induced integrin internalization and degradation as mechanistic consequences of endothelial Ang-2 stimulation.
Thomas
Markus
M
Joint Research Division Vascular Biology, Medical Faculty Mannheim (CBTM), Heidelberg University, D-69120 Heidelberg, Germany.
Felcht
Moritz
M
Kruse
Karoline
K
Kretschmer
Stella
S
Deppermann
Carleen
C
Biesdorf
Andreas
A
Rohr
Karl
K
Benest
Andrew V
AV
Fiedler
Ulrike
U
Augustin
Hellmut G
HG
D042702:Angiopoietin-2 / Q000378:metabolism*; D002450:Cell Communication; D002460:Cell Line; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D042787:Receptor, TIE-2 / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000737:chemistry
D042702:Angiopoietin-2; D039302:Integrin alphaVbeta3; D025801:Ubiquitin; D042787:Receptor, TIE-2