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Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling
Open accessAbstract
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.
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“Recent studies have demonstrated that beyond the primary signaling mode through TIE2, ANGPTs can also signal via integrins to modulate vascular responses (13, 21–25).”
From Inactive β1-integrin acts as a junctional scaffold for angiopoietin/TIE2/FOXO1 signaling (2026) · cites this paper as [21]
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“Integrins, which regulate endothelial cell–cell and cell–matrix interactions, have been identified as alternative receptors for the angiopoietins in certain Tie2-negative non-endothelial cells22232425, and in the endothelial tip cells of angiogenic vessel sprouts, which express low levels of Tie2 (refs 26, 27).”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [27]
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“Our results differentiating between Ang1- and Ang2-mediated β1-integrin activation in the absence of Tie2 are in line with Ang2-integrin signalling in the endothelial tip cells, which express high Ang2 but low Tie2 levels27.”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [27]
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Metadata
- Authors
- Felcht, M., Luck, R., Schering, A., Seidel, P., Srivastava, K., Hu, J., Bartol, A., Kienast, Y., Vettel, C., Loos, E. K., Kutschera, S., Bartels, S., Appak, S., Besemfelder, E., Terhardt, D., Chavakis, E., Wieland, T., Klein, C., Thomas, M., Uemura, A., Goerdt, S., & Augustin, H. G.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Goethe University Frankfurt (DE)
- Corresponding author
- Augustin, Hellmut G.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2012-06-01
- Volume
- 122
- Issue
- 6
- Pages
- 1991-2005
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3366398
- OpenAlex
- W2157985193
- Cited by
- 479
- References
- 50
- Citations by year
- 2026: 20 · 2025: 33 · 2024: 28 · 2023: 44 · 2022: 29 · 2021: 21 · 2020: 31 · 2019: 36 · 2018: 37 · 2017: 40 · 2016: 40 · 2015: 37 · 2014: 41 · 2013: 30 · 2012: 12
- FWCI
- 15.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft (Project B6, SFB873, SFB‐TR23)
- Aventis Foundation
- Japan Society for the Promotion of Science (22689046)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- angiopoietin-2, angiogenesis, Tie2, integrin signaling, FAK phosphorylation, Rac1 activation, sprouting angiogenesis, endothelial cells, tumor angiogenesis
- MeSH terms
- Animals, Female, Humans, Male, Melanoma, Neoplasm Proteins, Neovascularization, Pathologic, Neuropeptides, Phosphorylation, Signal Transduction, Down-Regulation, Integrins, rac GTP-Binding Proteins, Receptor Protein-Tyrosine Kinases, rac1 GTP-Binding Protein, Angiopoietin-2, Endothelial Cells, Receptor, TIE-2, Mice, Focal Adhesion Kinase 1
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