ArticleProceedings of the National Academy of Sciences of the United States of America2017
Dimerization of Tie2 mediated by its membrane-proximal FNIII domains.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- Structural organization of TAM receptor ectodomains.The Biochemical journal · 2026Article
- Inactive β1-integrin acts as a junctional scaffold for angiopoietin/TIE2/FOXO1 signaling.The Journal of clinical investigation · 2026Article
- Ang-1 and VEGF: central regulators of angiogenesis.Molecular and cellular biochemistry · 2025Review
- Auto- and Hetero-Catalytic Processing of the N-Terminal Propeptide Promotes the C-Terminal Fibronectin Type III Domain-Mediated Dimerization of a Thermostable Vpr-like Protease.Applied and environmental microbiology · 2022Article
- LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition.Nature immunology · 2022Article
- F-domain valency determines outcome of signaling through the angiopoietin pathway.EMBO reports · 2021Article
- Update Overview of the Role of Angiopoietins in Lung Cancer.Medicina (Kaunas, Lithuania) · 2021Review
- Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody.Nature communications · 2021Article
- Ang2 inhibitors and Tie2 activators: potential therapeutics in perioperative treatment of early stage cancer.EMBO molecular medicine · 2021Review
- Screening and Functional Analysis of TEK Mutations in Chinese Children With Primary Congenital Glaucoma.Frontiers in genetics · 2021Article
- Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis.eLife · 2020Article
- Insulin and epidermal growth factor receptor family members share parallel activation mechanisms.Protein science : a publication of the Protein Society · 2020Review
- The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye.International journal of retina and vitreous · 2020Review
- Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Angiopoietin-1 is required for Schlemm's canal development in mice and humans.The Journal of clinical investigation · 2017Article
- Therapeutic targeting of the angiopoietin-TIE pathway.Nature reviews. Drug discovery · 2017Review
- Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Role of Angiopoietin/Tie2 System in Sepsis: A Potential Therapeutic Target.Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/HemostasisReview
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Tie1 and Tie2, members of the tyrosine kinase family with immunoglobulin and EGF homology domains, are receptor tyrosine kinases found primarily in endothelial cells with key roles in development and maintenance of the vasculature and in angiogenesis. They are attractive targets for therapeutic intervention in tumor angiogenesis, inflammation, and sepsis. Tie2 is regulated directly by the multimeric angiopoietin (Ang) ligands, with Ang1 being its primary activator. Structural studies have shown how Angs bind to the Tie2 ligand-binding region, but do not explain Tie2 activation and suggest a passive role for the Tie2 extracellular region (ECR) in ligand-induced receptor dimerization. Here we show that the Tie2 ECR forms strong dimers even in the absence of bound ligand. Dimerization is mediated by membrane-proximal fibronectin type III (FNIII) domains that were omitted in previous structural studies. We describe a 2.5-Å resolution X-ray crystal structure of the membrane-proximal three Tie2 FNIII domains, Tie2(FNIIIa-c), revealing two possible dimerization modes that primarily involve the third FNIII domain, FNIIIc. Mutating these dimer interfaces implicates one of them (dimer 1) in soluble Tie2 (sTie2) dimerization in solution but suggests that both could play a role in Ang1-induced Tie2 activation, possibly modulated by Tie1. Through small-angle X-ray scattering studies of sTie2 dimers in solution and modeling based on crystal structures, we suggest that Ang1 binding may cross-link Tie2 dimers into higher-order oligomers, potentially explaining how Tie2 is differentially clustered following ligand engagement in different cellular contexts. Our results also firmly implicate FNIII domain-mediated interactions in Tie2 activation, identifying a potential Achilles' heel for therapeutic inhibition.
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