The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Integrins in cancer: biological implications and therapeutic opportunities
Desgrosellier, J. S., & Cheresh, D. A. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2748 · Cited by 3,815
Angiopoietin-2, a Natural Antagonist for Tie2 That Disrupts in vivo Angiogenesis
Maisonpierre, P. C., Suri, C., Jones, P. F., Bartunkova, S., Wiegand, S. J., Radziejewski, C., Compton, D., McClain, J., Aldrich, T. H., Papadopoulos, N., et al. (1997) · Science · doi:10.1126/science.277.5322.55 · Cited by 3,570
Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis
Suri, C., Jones, P. F., Patan, S., Bartunkova, S., Maisonpierre, P. C., Davis, S. H., Sato, T. N., & Yancopoulos, G. D. (1996) · Cell · doi:10.1016/s0092-8674(00)81813-9 · Cited by 2,872
Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation
Sato, T. N., Tozawa, Y., Deutsch, U., Wolburg‐Buchholz, K., Fujiwara, Y., Gendron‐Maguire, M., Gridley, T., Wolburg, H., Risau, W., & Qin, Y. (1995) · Nature · doi:10.1038/376070a0 · Cited by 1,821
Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system
Augustin, H. G., Koh, G. Y., Thurston, G., & Alitalo, K. K. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2639 · Cited by 1,512
Self-citationGale, N. W., Thurston, G., Hackett, S. F., Renard, R. A., Wang, Q., McClain, J., Martin, C., Witte, C. L., Witte, M. H., Jackson, D. G., et al. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00217-4 · Cited by 1,017
Random versus directionally persistent cell migration
Petrie, R. J., Doyle, A. D., & Yamada, K. M. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2729 · Cited by 995
Dumont, D. J., Gradwohl, G., Fong, G. H., Puri, M. C., Gertsenstein, M., Auerbach, A., & Breitman, M. L. (1994) · Genes & Development · doi:10.1101/gad.8.16.1897 · Cited by 985
Fiedler, U., Reiss, Y., Scharpfenecker, M., Grunow, V., Koidl, S., Thurston, G., Gale, N. W., Witzenrath, M., Rosseau, S., Suttorp, N., et al. (2006) · Nature Medicine · doi:10.1038/nm1351 · Cited by 933
Self-citationMazzieri, R., Pucci, F., Moi, D., Zonari, E., Ranghetti, A., Berti, A., Politi, L. S., Gentner, B., Brown, J. L., Naldini, L., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.02.005 · Cited by 639
Reynolds, A. R., Hart, I. R., Watson, A. R., Welti, J. C., Silva, R. G., Robinson, S. D., Violante, G. D., Gourlaouen, M., Salih, M., Jones, M., et al. (2009) · Nature Medicine · doi:10.1038/nm.1941 · Cited by 500
Schäfer, W. M., Regula, J. T., Bähner, M., Schanzer, J., Croasdale, R., Dürr, H., Gassner, C., Georges, G. J., Kettenberger, H., Imhof-Jung, S., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019002108 · Cited by 489
Self-citationTargeting the ANGPT–TIE2 pathway in malignancy
Huang, H., Bhat, A., Woodnutt, G., & Lappe, R. W. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2894 · Cited by 479
Identification and functional analysis of endothelial tip cell–enriched genes
del Toro, R., Prahst, C., Mathivet, T., Siegfried, G., Kaminker, J. S., Larrivee, B., Breant, C., Duarte, A., Takakura, N., Fukamizu, A., et al. (2010) · Blood · doi:10.1182/blood-2010-02-270819 · Cited by 474
Saharinen, P., Eklund, L., Miettinen, J., Wirkkala, R., Anisimov, A., Winderlich, M., Nottebaum, A., Vestweber, D., Deutsch, U., Koh, G. Y., et al. (2008) · Nature Cell Biology · doi:10.1038/ncb1715 · Cited by 471
Tumor-Associated Endothelial Cells with Cytogenetic Abnormalities
Hida, K., Hida, Y., Amin, D. N., Flint, A., Panigrahy, D., Morton, C. C., & Klagsbrun, M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1567 · Cited by 470
Tie2 Expression and Phosphorylation in Angiogenic and Quiescent Adult Tissues
Wong, A. L., Haroon, Z. A., Werner, S., Dewhirst, M. W., Greenberg, C. S., & Peters, K. G. (1997) · Circulation Research · doi:10.1161/01.res.81.4.567 · Cited by 417
Angiopoietin 2 Is a Partial Agonist/Antagonist of Tie2 Signaling in the Endothelium
Yuan, H. T., Khankin, E. V., Karumanchi, S. A., & Parikh, S. M. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01472-08 · Cited by 383
Scharpfenecker, M., Fiedler, U., Reiss, Y., & Augustin, H. G. (2005) · Journal of Cell Science · doi:10.1242/jcs.01653 · Cited by 382
Self-citationKorff, T., Kimmina, S., Martiny‐Baron, G., & Augustin, H. G. (2001) · The FASEB Journal · doi:10.1096/fj.00-0139com · Cited by 367
Self-citationLuque, A., Gómez, M., Puzon-McLaughlin, W., Takada, Y., Sánchez‐Madrid, F., & Cabañas, C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.19.11067 · Cited by 296
Integrin structures and conformational signaling
Luo, B., & Springer, T. A. (2006) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2006.08.005 · Cited by 296
Strasser, G. A., Kaminker, J. S., & Tessier‐Lavigne, M. (2010) · Blood · doi:10.1182/blood-2009-07-230284 · Cited by 295
Direct Cell Adhesion to the Angiopoietins Mediated by Integrins
Carlson, T. R., Feng, Y., Maisonpierre, P. C., Mrksich, M., & Morla, A. O. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100282200 · Cited by 265
Lenter, M., Uhlig, H., Hamann, A., Jenö, P., Imhof, B. A., & Vestweber, D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.19.9051 · Cited by 264
Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells
Daly, C., Pasnikowski, E. M., Burova, E., Wong, V., Aldrich, T. H., Griffiths, J., Ioffe, E., Daly, T. J., Fandl, J. P., Papadopoulos, N., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607538103 · Cited by 254
Complementary Actions of Inhibitors of Angiopoietin-2 and VEGF on Tumor Angiogenesis and Growth
Hashizume, H., Falcón, B. L., Kuroda, T., Bałuk, P., Coxon, A., Yu, D., BREADY, J. V., Oliner, J. D., & McDonald, D. M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-1977 · Cited by 253
Spheroid-based engineering of a human vasculature in mice
Alajati, A., Laib, A. M., Weber, H., Boos, A. M., Bartol, A., Ikenberg, K., Korff, T., Zentgraf, H., Obodozie, C., Graeser, R., et al. (2008) · Nature Methods · doi:10.1038/nmeth.1198 · Cited by 208
Self-citationAngiopoietin‐2 plays an important role in retinal angiogenesis
Hackett, S. F., Wiegand, S. J., Yancopoulos, G. D., & Campochiaro, P. A. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10128 · Cited by 202
Angiopoietin-1 Promotes Cardiac and Skeletal Myocyte Survival Through Integrins
Dallabrida, S. M., Ismail, N. S., Oberle, J., Himes, B. E., & Rupnick, M. A. (2005) · Circulation Research · doi:10.1161/01.res.0000158285.57191.60 · Cited by 195
Angiopoietin-2 Stimulates Breast Cancer Metastasis through the α5β1 Integrin-Mediated Pathway
Imanishi, Y., Hu, B., Jarzynka, M. J., Guo, P., Elishaev, E., Bar-Joseph, I., & Cheng, S.-Y. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4100 · Cited by 190
Nasarre, P., Thomas, M., Kruse, K., Helfrich, I., Wolter, V., Deppermann, C., Schadendorf, D., Thurston, G., Fiedler, U., & Augustin, H. G. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3030 · Cited by 177
Self-citationEndothelial α5 and αv integrins cooperate in remodeling of the vasculature during development
van der Flier, A., Badu-Nkansah, K. A., Whittaker, C. A., Crowley, D. G., Bronson, R. T., Lacy‐Hulbert, A., & Hynes, R. O. (2010) · Development · doi:10.1242/dev.049551 · Cited by 173
Molecular photoacoustic imaging of angiogenesis with integrin‐targeted gold nanobeacons
Pan, D., Pramanik, M., Senpan, A., Allen, J. S., Zhang, H., Wickline, S. A., Wang, L. V., & Lanza, G. M. (2010) · The FASEB Journal · doi:10.1096/fj.10-171728 · Cited by 173
Hu, B., Jarzynka, M. J., Guo, P., Imanishi, Y., Schlaepfer, D. D., & Cheng, S. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-1149 · Cited by 172
Koh, Y. J., Kim, H.-Z., Hwang, S.-I., Lee, J. E., Oh, N., Jung, K., Kim, M., Kim, K. E., Kim, H., Lim, N. K., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.07.001 · Cited by 157
Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis
Stenzel, D., Lundkvist, A., Sauvaget, D., Busse, M., Graupera, M., van der Flier, A., Wijelath, E. S., Murray, J., Sobel, M., Costell, M., et al. (2011) · Development · doi:10.1242/dev.071381 · Cited by 154
Spheroid-based human endothelial cell microvessel formation in vivo
Laib, A. M., Bartol, A., Alajati, A., Korff, T., Weber, H., & Augustin, H. G. (2009) · Nature Protocols · doi:10.1038/nprot.2009.96 · Cited by 132
Self-citationStructural basis for ligand recognition by integrins
Takagi, J. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.09.002 · Cited by 124
Angiopoietin-2 Impairs Revascularization After Limb Ischemia
Reiss, Y., Droste, J., Heil, M., Tribulova, S., Schmidt, M. H. H., Schaper, W. K. A., Dumont, D., & Plate, K. H. (2007) · Circulation Research · doi:10.1161/circresaha.106.143594 · Cited by 111
Thomas, M., Felcht, M., Kruse, K., Kretschmer, S., Deppermann, C., Biesdorf, A., Rohr, K., Benest, A. V., Fiedler, U., & Augustin, H. G. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.097543 · Cited by 101
Self-citationTie2 vascular endothelial receptor expression and function in hepatocellular carcinoma
Tanaka, S., Sugimachi, K., Yamashita, Y., Ohga, T., Shirabe, K., Shimada, M., Wands, J. R., & Sugimachi, K. (2002) · Hepatology · doi:10.1053/jhep.2002.32535 · Cited by 91
Tressel, S. L., Huang, R., Tomsen, N., & Jo, H. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.150920 · Cited by 89
Wang, Z., Collighan, R. J., Gross, S. R., Danen, E. H. J., Orend, G., Telci, D., & Griffin, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.123703 · Cited by 83
Abai, B., Thayer, D., & Glat, P. M. (2004) · Plastic & Reconstructive Surgery · doi:10.1097/01.prs.0000129078.41960.92 · Cited by 70
Besides adhesion: new perspectives of integrin functions in angiogenesis
Serini, G., Napione, L., Arese, M., & Bussolino, F. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn045 · Cited by 61
Heterogeneity of Tie2 Expression in Tumor Microcirculation
Fathers, K. E., Stone, C., Minhas, K., Marriott, J. J. A., Greenwood, J. D., Dumont, D., & Coomber, B. L. (2005) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)61256-4 · Cited by 38
A Human Neutralizing Antibody Specific to Ang‐2 Inhibits Ocular Angiogenesis
Rennel, E., Regula, J. T., Harper, S. J., Thomas, M., Klein, C., & Bates, D. O. (2011) · Microcirculation · doi:10.1111/j.1549-8719.2011.00120.x · Cited by 36
Self-citationSun, W. Y., Pitson, S. M., & Bonder, C. S. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.091016 · Cited by 34
Bezuidenhout, L. M., Zilla, P., & Davies, N. H. (2009) · Inflammation · doi:10.1007/s10753-009-9148-9 · Cited by 17
Flagged first, then by citations
Cited by
Sorted by citations
Pericytes of the neurovascular unit: key functions and signaling pathways
Sweeney, M. D., Ayyadurai, S., & Zlokovic, B. V. (2016) · Nature Neuroscience · doi:10.1038/nn.4288 · Cited by 1,125
Therapeutic strategies for enhancing angiogenesis in wound healing
Veith, A. P., Henderson, K., Spencer, A., Sligar, A. D., & Baker, A. B. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.09.010 · Cited by 1,047
Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology
Augustin, H. G., & Koh, G. Y. (2017) · Science · doi:10.1126/science.aal2379 · Cited by 790
Self-citationMechanisms of macular edema: Beyond the surface
Daruich, A., Matet, A., Moulin, A., Kowalczuk, L., Nicolas, M., Sellam, A., Rothschild, P.-R., Omri, S., Gélizé, E., Jonet, L., et al. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.10.006 · Cited by 744
Nanocomposite scaffolds for accelerating chronic wound healing by enhancing angiogenesis
Nosrati, H., Khouy, R. A., Nosrati, A., Khodaei, M., Banitalebi-Dehkordi, M., Ashrafi-Dehkordi, K., Sanami, S., & Alizadeh, Z. (2021) · Journal of Nanobiotechnology · doi:10.1186/s12951-020-00755-7 · Cited by 729
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
