Abstract
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.
Highlights
Angiogenesis and blood vessel maintenance are orchestrated by the coordinated interplay of multiple vascular receptor tyrosine kinase signaling pathways, including the VEGF/VEGFR,5 the ephrin/Eph, and the angiopoietin/Tie pathways
Ang-1 and Ang-2 Induce Translocation of Tie2 and 3 Integrins to Cell-Cell Junctions—It is well established that both Ang-1 and Ang-2 induce in contacting endothelial cell (EC) translocation of their receptor Tie2 to cell-cell junctions (11, 12)
We aimed at examining if angiopoietins induced co-localization of Tie2 and 3 integrins
Summary
Angiogenesis and blood vessel maintenance are orchestrated by the coordinated interplay of multiple vascular receptor tyrosine kinase signaling pathways, including the VEGF/VEGFR,5 the ephrin/Eph, and the angiopoietin/Tie pathways. Only Ang-2 stimulation induced complex formation between Tie2 and ␣v3 integrin. The analyses did not reveal increasing co-localization between Tie2 or 3 integrins with the diffusely distributed CD31 on the cell surface upon angiopoietin stimulation in the z-sticks (Fig. 1A, bar 1– 6).
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