Affinage

ANGPT1

Angiopoietin-1 · UniProt Q15389

Length
498 aa
Mass
57.5 kDa
Annotated
2026-06-09
27 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANGPT1 is a secreted, multimerizing glycoprotein ligand that signals through Tie receptor tyrosine kinases to stabilize the vasculature and regulate angiogenesis and lymphangiogenesis (PMID:28601681, PMID:38742432). Efficient receptor engagement depends on its higher-order multimerization: a patient missense mutation (p.A119S) that impairs multimer formation reduces TIE2 binding and is associated with compromised vascular integrity (PMID:28601681). Acting on endothelial cells, ANGPT1 activates the PI3K/Akt pathway and reinforces tight and adherens junctions—modulating claudin-5, VE-cadherin, integrin αvβ3, and β-catenin—to control vascular permeability and barrier function, including when delivered via pericyte-derived extracellular vesicles (PMID:25485810, PMID:39940043). In zebrafish, Angpt1 binds specifically to Tie1 to drive endothelial migration, proliferation, and lymphatic specification in part through cross-talk with Vegfc/Vegfr3 signaling (PMID:38742432). ANGPT1 transcription is gated by opposing regulators: a KDM3B–SMRT co-repressor complex represses the ANGPT1 promoter independently of KDM3B demethylase activity, while RXRα activates the promoter downstream of retinoic acid metabolism in pericytes to promote vascular normalization (PMID:25413303, PMID:39075504). Beyond the vasculature, ANGPT1 functions in niche and immune contexts: perivascular ANGPT1 production driven by β-adrenergic signaling maintains skeletal muscle stem cell quiescence (PMID:40752496), osteoblastic Angpt1/Tie2 signaling supports hematopoietic stem cell reconstitution (PMID:23149415), an autocrine Angpt1/Tek loop sustains RUNX1-MECOM leukemia cell growth (PMID:40570741), and an ANGPT1/PI3K/AKT axis downstream of HMGB2 enhances NK cell cytotoxicity (PMID:41280896).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2012 Medium

    Established that enhanced Angpt1/Tie2 signaling from a stromal (osteoblast) compartment shapes hematopoietic stem cell behavior, extending ANGPT1's role beyond endothelium into niche regulation.

    Evidence Col1a1-Cre × COMP-Angpt1 conditional transgenic mice with bone marrow transplantation/reconstitution assays

    PMID:23149415

    Open questions at the time
    • Gain-of-function overexpression does not establish requirement of endogenous Angpt1
    • Receptor and downstream signaling in the niche not directly mapped
  2. 2015 Medium

    Identified a transcriptional brake on ANGPT1: a KDM3B–SMRT complex represses the promoter independently of demethylase activity, addressing how ANGPT1 expression is set in cells.

    Evidence Reporter assays, KDM3B–SMRT co-IP, ChIP at the ANGPT1 promoter, and KDM3B-knockdown proliferation/motility assays

    PMID:25413303

    Open questions at the time
    • Functional consequence on secreted ANGPT1 protein and Tie2 signaling not shown
    • Cell-type generality of the repressor complex unknown
  3. 2016 Medium

    Showed mechanistically that ANGPT1 controls vascular permeability by tuning junctional and cytoskeletal proteins, connecting the ligand to endothelial barrier maintenance.

    Evidence ANGPT1-neutralizing antibody in CAM assay and endothelial cell culture with immunofluorescence of junction and cytoskeletal markers

    PMID:25485810

    Open questions at the time
    • Direct receptor dependence (Tie2) not isolated in this assay
    • Quantitative ordering of junction protein changes not resolved
  4. 2017 Medium

    Linked ANGPT1 multimerization directly to receptor binding and human vascular pathology by characterizing a multimerization-impairing missense mutation.

    Evidence Patient plasma protein analysis plus recombinant mutant (p.A119S) expression and TIE2 binding assay

    PMID:28601681

    Open questions at the time
    • Single variant; structural basis of multimerization not defined
    • Causal chain from reduced binding to angioedema phenotype inferred, not reconstituted
  5. 2024 High

    Resolved a receptor specificity question by demonstrating that, in zebrafish lymphatic development, Angpt1 acts as a Tie1 ligand that drives lymphatic specification via Vegfc/Vegfr3 cross-talk.

    Evidence Comprehensive zebrafish mutant analysis, ligand-binding assays, live EGFP-Foxo1a nuclear-import reporter, and genetic epistasis with Vegfc/Vegfr3

    PMID:38742432

    Open questions at the time
    • Whether mammalian ANGPT1 uses Tie1 equivalently not established here
    • Direct biochemical affinity comparison across Tie receptors not quantified
  6. 2024 Medium

    Defined an activating transcriptional input to ANGPT1: RXRα binds the promoter downstream of CCL28-reprogrammed retinoic acid metabolism in pericytes to promote tumor vascular normalization.

    Evidence CCL28 in vivo overexpression/knockout, pericyte RNA-seq, ChIP-qPCR for RXRα at the ANGPT1 promoter, and LC-MS metabolomics

    PMID:39075504

    Open questions at the time
    • Direct demonstration that the induced ANGPT1 is secreted and acts on adjacent endothelium via Tie2 not isolated
    • Generalizability beyond the tumor/pericyte context unknown
  7. 2025 Medium

    Demonstrated an autocrine Angpt1/Tek loop in RUNX1-MECOM leukemia, showing ANGPT1 signaling sustains malignant cell growth and is druggable via HDAC inhibition.

    Evidence RT-PCR array, Western blot co-expression, Angpt1 stimulation with phospho-Tek/phospho-Akt detection, HDAC inhibitor treatment, in vitro proliferation and in vivo transplantation

    PMID:40570741

    Open questions at the time
    • Direct binding of autocrine Angpt1 to Tek not separately confirmed
    • HDAC inhibitor effects may be only partly through this loop
  8. 2025 Medium

    Showed perivascular ANGPT1, driven by sympathetic β-adrenergic input, maintains skeletal muscle stem cell quiescence, establishing a neuro-vascular-niche function.

    Evidence Sympathetic denervation model, pharmacologic and genetic β-adrenergic modulation, niche imaging, and Angpt1 loss-of-function

    PMID:40752496

    Open questions at the time
    • Receptor mediating the quiescence effect not pinpointed
    • Whether effect is direct on stem cells or via vasculature not fully separated
  9. 2025 Medium

    Demonstrated extracellular-vesicle delivery of Angpt1 as a functional mode of action, with PCEV-borne Angpt1 driving endothelial PI3K/Akt activation and barrier protection in sepsis.

    Evidence PCEV proteomics, Angpt1 knockdown in PCEVs, CLP sepsis rat model, in vitro endothelial assays, phospho-PI3K/Akt Western blots

    PMID:39940043

    Open questions at the time
    • Receptor engaged by EV-delivered Angpt1 not defined
    • Contribution relative to soluble secreted Angpt1 not quantified
  10. 2025 Medium

    Placed ANGPT1 in an immune-effector pathway, showing an ANGPT1/PI3K/AKT axis downstream of HMGB2 controls NK cell cytotoxicity.

    Evidence CRISPR/Cas9 and RNAi of HMGB2, ANGPT1 knockdown in HMGB2-KO cells, flow cytometry for cytotoxic markers, tumor lysis assay

    PMID:41280896

    Open questions at the time
    • Whether ANGPT1 acts cell-autonomously via a Tie receptor in NK cells not shown
    • Mechanism of HMGB2 repression of ANGPT1 not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ANGPT1 receptor choice (Tie2 vs Tie1) and signaling output are specified across mammalian tissues, and which receptor mediates its non-endothelial niche and immune functions.
  • Mammalian Tie1 ligand role for ANGPT1 not established
  • Receptor identity in muscle stem cell, NK cell, and EV-mediated contexts undefined
  • Structural basis of multimerization-dependent binding not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1474165 Reproduction 1
Partners

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 A missense mutation in ANGPT1 (p.A119S) reduces the formation of multimeric forms of the protein and impairs its ability to bind its natural receptor TIE2 (tunica interna endothelial cell kinase 2), establishing a mechanistic link between ANGPT1 multimerization/receptor binding and maintenance of vascular integrity (hereditary angioedema). Protein analysis of patient plasma, recombinant mutant protein expression, receptor binding assay The Journal of allergy and clinical immunology Medium 28601681
2015 The histone H3K9 demethylase KDM3B transcriptionally represses ANGPT1 independently of its JmjC-domain demethylase activity, acting via interaction with the co-repressor SMRT to form a repressor complex at the ANGPT1 promoter; KDM3B depletion increases cell proliferation and motility. Reporter assay, co-immunoprecipitation (KDM3B–SMRT interaction), chromatin immunoprecipitation at ANGPT1 promoter, MTT and wound-healing assays with KDM3B knockdown BMB reports Medium 25413303
2012 Enhanced Angpt1/Tie2 signaling in osteoblasts (via COMP-Angpt1 transgenic overexpression) affects hematopoietic lineage differentiation during early development and increases the long-term bone marrow reconstitution ability of LSK (Lin−Sca-1+c-Kit+) hematopoietic stem cells. Conditional transgenic mouse model (Col1a1-Cre × COMP-Angpt1), peripheral blood analysis, bone marrow transplantation/reconstitution assay Biochemical and biophysical research communications Medium 23149415
2016 Inhibition of ANGPT1 in follicular fluid from OHSS patients (using a neutralizing antibody) restores vascular branch points, integrin αvβ3 levels, claudin-5, VE-cadherin, and phosphorylated β-catenin, and partially reverses actin redistribution in endothelial cells, demonstrating that ANGPT1 modulates tight and adherens junction proteins to regulate vascular permeability. ANGPT1-neutralizing antibody in chorioallantoic membrane (CAM) assay and endothelial cell culture; immunofluorescence of junction proteins and cytoskeletal markers Reproduction, fertility, and development Medium 25485810
2024 In zebrafish, Angpt1 binds specifically to Tie1 (not other Tie receptors) as a ligand, activates Tie1 signaling (monitored by nuclear exclusion of EGFP-Foxo1a in sprouting endothelial cells), promotes endothelial cell migration and proliferation, and drives lymphatic specification during early lymphangiogenesis, at least in part by modulating Vegfc/Vegfr3 signaling. Comprehensive zebrafish mutant analysis (angpt1, tie1, other angiopoietin/Tie receptor mutants), ligand-binding assay, live EGFP-Foxo1a nuclear-import reporter, genetic epistasis with Vegfc/Vegfr3 Development (Cambridge, England) High 38742432
2025 In RUNX1-MECOM-expressing leukemia cells, Angpt1 and its receptor Tek (Tie2) are co-expressed and form an autocrine signaling loop: exogenous Angpt1 stimulation phosphorylates endogenous Tek, which activates downstream Akt. HDAC inhibitors (TSA and VPA) downregulate both Tek and Angpt1 expression, disrupting this loop and inhibiting leukemia cell growth via cell-cycle arrest and apoptosis. Quantitative RT-PCR array, Western blot for Angpt1/Tek protein co-expression, Angpt1 stimulation with phospho-Tek and phospho-Akt detection, HDAC inhibitor treatment, in vitro proliferation and in vivo transplantation assay Leukemia research Medium 40570741
2025 Sympathetic innervation stimulates β-adrenergic receptors on perivascular cells to drive Angpt1 production; perivascular-derived Angpt1 maintains the quiescent state of post-natal skeletal muscle stem cells. Sympathetic denervation reduces perivascular Angpt1, leading to vascular remodeling, depletion of the muscle stem cell pool, and impaired tissue repair. Sympathetic denervation model, pharmacologic and genetic β-adrenergic receptor modulation, immunofluorescence/live imaging of muscle stem cell niche, loss-of-function for Angpt1 Developmental cell Medium 40752496
2024 In pericytes, CCL28 reprograms retinoic acid (RA) metabolism and increases ANGPT1 expression via RXRα transcriptional activation of the ANGPT1 promoter (validated by ChIP-qPCR), thereby enhancing endothelial cell stability and promoting tumor vascular normalization after anti-angiogenesis therapy. CCL28 overexpression/knockout in vivo models, RNA sequencing of pericytes, ChIP-qPCR for RXRα binding to ANGPT1 promoter, LC-MS metabolomics, Western blot Journal of experimental & clinical cancer research Medium 39075504
2025 Angpt1 carried by pericyte-derived extracellular vesicles (PCEVs) activates the PI3K/Akt pathway in endothelial cells; knockdown of Angpt1 in PCEVs suppresses PI3K/Akt activation and abolishes the protective effects on intestinal vascular barrier function and pericyte recruitment in sepsis. Proteomic analysis of PCEVs, Angpt1 knockdown in PCEVs, CLP sepsis rat model, in vitro endothelial assays, Western blot for phospho-PI3K and phospho-Akt Stem cell research & therapy Medium 39940043
2025 HMGB2 ablation in NK cells induces ANGPT1 expression, which activates the PI3K/AKT pathway; ANGPT1 knockdown in HMGB2-KO NK cells reduces PI3K/AKT activation and diminishes enhanced NK cytotoxicity (granzyme B, perforin, IFN-γ, TNF-α release and tumor lysis), establishing an ANGPT1/PI3K/AKT axis downstream of HMGB2 in NK cell function. CRISPR/Cas9 KO and RNA interference of HMGB2, ANGPT1 knockdown in KO-HMGB2 cells, flow cytometry for cytotoxic markers, tumor lysis assay Frontiers in immunology Medium 41280896

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. The Journal of allergy and clinical immunology 217 28601681
2021 Exosomal lncRNA-H19 promotes osteogenesis and angiogenesis through mediating Angpt1/Tie2-NO signaling in CBS-heterozygous mice. Theranostics 117 34335960
2016 Dual targeting of ANGPT1 and TGFBR2 genes by miR-204 controls angiogenesis in breast cancer. Scientific reports 63 27703260
2020 Blocking exosomal miRNA-153-3p derived from bone marrow mesenchymal stem cells ameliorates hypoxia-induced myocardial and microvascular damage by targeting the ANGPT1-mediated VEGF/PI3k/Akt/eNOS pathway. Cellular signalling 47 33164880
2021 Exosomal miR-3682-3p Suppresses Angiogenesis by Targeting ANGPT1 via the RAS-MEK1/2-ERK1/2 Pathway in Hepatocellular Carcinoma. Frontiers in cell and developmental biology 31 33869178
2021 Transplantation of 3D bio-printed cardiac mesh improves cardiac function and vessel formation via ANGPT1/Tie2 pathway in rats with acute myocardial infarction. Biofabrication 19 34404035
2017 Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients. PloS one 19 28045923
2017 VEGF, ANGPT1, ANGPT2, and MMP-9 expression in the autologous hematopoietic stem cell transplantation and its impact on the time to engraftment. Annals of hematology 18 28956132
2022 Knockdown of CDR1as Decreases Differentiation of Goat Skeletal Muscle Satellite Cells via Upregulating miR-27a-3p to Inhibit ANGPT1. Genes 15 35456469
2012 Enhanced Angpt1/Tie2 signaling affects the differentiation and long-term repopulation ability of hematopoietic stem cells. Biochemical and biophysical research communications 15 23149415
2015 Transcriptional repression of ANGPT1 by histone H3K9 demethylase KDM3B. BMB reports 13 25413303
2016 Inhibition of angiopoietin-1 (ANGPT1) affects vascular integrity in ovarian hyperstimulation syndrome (OHSS). Reproduction, fertility, and development 12 25485810
2024 Pericytes recruited by CCL28 promote vascular normalization after anti-angiogenesis therapy through RA/RXRA/ANGPT1 pathway in lung adenocarcinoma. Journal of experimental & clinical cancer research : CR 11 39075504
2014 Clonal Dominance With Retroviral Vector Insertions Near the ANGPT1 and ANGPT2 Genes in a Human Xenotransplant Mouse Model. Molecular therapy. Nucleic acids 9 25291142
2021 MiR-452 Regulates C2C12 Myoblast Proliferation and Differentiation via Targeting ANGPT1. Frontiers in genetics 8 33777108
2019 Sex-specific SNP-SNP interaction analyses within topologically associated domains reveals ANGPT1 as a novel tumor suppressor gene for lung cancer. Genes, chromosomes & cancer 8 31385379
2021 Immune-related gene ANGPT1 is an adverse biomarker for endometrial carcinoma. Translational cancer research 7 35116604
2025 Pericyte-derived extracellular vesicles improve vascular barrier function in sepsis via the Angpt1/PI3K/AKT pathway and pericyte recruitment: an in vivo and in vitro study. Stem cell research & therapy 6 39940043
2024 Angpt1 binding to Tie1 regulates the signaling required for lymphatic vessel development in zebrafish. Development (Cambridge, England) 6 38742432
2021 Genetic Variants of ANGPT1, CD39, FGF2 and MMP9 Linked to Clinical Outcome of Bevacizumab Plus Chemotherapy for Metastatic Colorectal Cancer. International journal of molecular sciences 6 33573134
2025 Sympathetic innervation maintains the murine quiescent skeletal muscle stem cell pool via perivascular-derived Angpt1. Developmental cell 4 40752496
2021 ANGPT1 methylation and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients. Epigenetics communications 4 35359917
2025 High expression and regulatory mechanisms of ANGPT1 and HOXA3 in acute myeloid leukemia. Bulletin du cancer 3 40107921
2023 Polymorphisms in TIE2 and ANGPT-1 genes are associated with protection against diabetic retinopathy in a Brazilian population. Archives of endocrinology and metabolism 3 37249455
2025 HDAC inhibitors repress Tek and Angpt1 expression and proliferation in RUNX1-MECOM-type leukemia cells. Leukemia research 2 40570741
2025 NK cell function down regulated by HMGB2 through ANGPT1/PI3K/AKT pathway and its effect on esophageal squamous carcinoma cells. Frontiers in immunology 1 41280896
2024 ANGPT1 promotes M1 macrophage polarization and inhibits lung adenocarcinoma progression by inhibiting the TGF-β signalling pathway. General physiology and biophysics 1 38477603

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