Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling
Angiopoietin-2 (ANG-2) is a key regulator of angiogenesis that exerts context-dependent effects on ECs. ANG-2 binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the responsiveness of ECs t...
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| Hauptverfasser: | , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
May 15, 2012
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| In: |
The journal of clinical investigation
Year: 2012, Jahrgang: 122, Heft: 6, Pages: 1991-2005 |
| ISSN: | 1558-8238 |
| DOI: | 10.1172/JCI58832 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1172/JCI58832
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| Verfasserangaben: | Moritz Felcht, Robert Luck, Alexander Schering, Philipp Seidel, Kshitij Srivastava, Junhao Hu, Arne Bartol, Yvonne Kienast, Christiane Vettel, Elias K. Loos, Simone Kutschera, Susanne Bartels, Sila Appak, Eva Besemfelder, Dorothee Terhardt, Emmanouil Chavakis, Thomas Wieland, Christian Klein, Markus Thomas, Akiyoshi Uemura, Sergij Goerdt, and Hellmut G. Augustin |
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| 520 | |a Angiopoietin-2 (ANG-2) is a key regulator of angiogenesis that exerts context-dependent effects on ECs. ANG-2 binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the responsiveness of ECs to exogenous cytokines. Recent data from tumors indicate that under certain conditions ANG-2 can also promote angiogenesis. However, the molecular mechanisms of dual ANG-2 functions are poorly understood. Here, we identify a model for the opposing roles of ANG-2 in angiogenesis. We found that angiogenesis-activated endothelium harbored a subpopulation of TIE2-negative ECs (TIE2lo). TIE2 expression was downregulated in angiogenic ECs, which abundantly expressed several integrins. ANG-2 bound to these integrins in TIE2lo ECs, subsequently inducing, in a TIE2-independent manner, phosphorylation of the integrin adaptor protein FAK, resulting in RAC1 activation, migration, and sprouting angiogenesis. Correspondingly, in vivo ANG-2 blockade interfered with integrin signaling and inhibited FAK phosphorylation and sprouting angiogenesis of TIE2lo ECs. These data establish a contextual model whereby differential TIE2 and integrin expression, binding, and activation control the role of ANG-2 in angiogenesis. The results of this study have immediate translational implications for the therapeutic exploitation of angiopoietin signaling. | ||
| 650 | 4 | |a Angiopoietin-2 | |
| 650 | 4 | |a Animals | |
| 650 | 4 | |a Down-Regulation | |
| 650 | 4 | |a Endothelial Cells | |
| 650 | 4 | |a Female | |
| 650 | 4 | |a Focal Adhesion Kinase 1 | |
| 650 | 4 | |a Humans | |
| 650 | 4 | |a Integrins | |
| 650 | 4 | |a Male | |
| 650 | 4 | |a Melanoma | |
| 650 | 4 | |a Mice | |
| 650 | 4 | |a Neoplasm Proteins | |
| 650 | 4 | |a Neovascularization, Pathologic | |
| 650 | 4 | |a Neuropeptides | |
| 650 | 4 | |a Phosphorylation | |
| 650 | 4 | |a rac GTP-Binding Proteins | |
| 650 | 4 | |a rac1 GTP-Binding Protein | |
| 650 | 4 | |a Receptor Protein-Tyrosine Kinases | |
| 650 | 4 | |a Receptor, TIE-2 | |
| 650 | 4 | |a Signal Transduction | |
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