Affinage

TIE1

Tyrosine-protein kinase receptor Tie-1 · UniProt P35590

Length
1138 aa
Mass
125.1 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIE1 is an endothelial-specific receptor tyrosine kinase that functions as a context-dependent modulator of TIE2 (TEK) signaling and is required cell-autonomously for blood vascular integrity and lymphatic development (PMID:8846781, PMID:7596437, PMID:10498691, PMID:10995770). TIE1 forms pre-formed heterotypic complexes with TIE2 through both intracellular domain contacts and membrane-proximal Fibronectin type III (Fn3) domains, the latter mediating heterodimerization via an intermolecular β-sheet structurally analogous to that driving TIE2 homodimerization (PMID:10995770, PMID:28396439). Although TIE1 displays negligible intrinsic kinase activity and does not autophosphorylate on its own, it is phosphorylated by angiopoietins (Ang1, Ang4, COMP-Ang1) in a strictly TIE2-dependent manner, and the TIE1:TIE2 stoichiometry tunes endothelial responsiveness to angiopoietins — TIE1 generally restrains TIE2 activation, and its expression level determines whether Ang2 acts as a TIE2 agonist or antagonist (PMID:15851516, PMID:17504972, PMID:22342979, PMID:20227369). This balance is set dynamically by regulated ectodomain shedding: ADAM17/γ-secretase-mediated cleavage of TIE1, stimulated by VEGF, TNFα, fluid shear stress, and PIEZO1 mechanosensing, raises the TIE2:TIE1 ratio and relieves TIE1's suppression of TIE2 signaling, including during acute endotoxemia (PMID:17728252, PMID:22235284, PMID:14500555, PMID:27548530, PMID:38747287). Where TIE1 does signal, it activates PI3K/Akt via Tyr1113 to promote endothelial survival and to control FOXO1 nuclear localization, and its loss drives Slug-dependent endothelial-mesenchymal transition (PMID:11865050, PMID:27548530, PMID:22421998). TIE1 also engages additional binding partners — LECT2, which disrupts TIE1-TIE2 heterodimers and favors TIE2 homodimerization, heparan sulfate glycosaminoglycans, which promote heterodimerization and TIE protein stability, and integrins α5β1/αVβ3, which cooperate to stimulate ERK/MAPK signaling (PMID:31474362, PMID:33020664, PMID:27695111). In the lymphatic vasculature TIE1 is required, partly through its intracellular domain and independently of TIE2, for LEC proliferation and survival, lymphangiogenesis, collecting vessel remodeling, and valve specification, and supports VEGF-C/VEGFR3-driven lymphangiogenesis by sustaining VEGFR3 surface presentation (PMID:19910638, PMID:20223757, PMID:24764452, PMID:25576926, PMID:35763346). TIE1 additionally contributes to vascular inflammation and atherogenesis at disturbed-flow sites (PMID:21383501, PMID:18448073).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Established that TIE1 is dispensable for vasculogenesis but cell-autonomously required for endothelial integrity and survival during angiogenic growth, defining its developmental role.

    Evidence Targeted gene disruption and chimeric analysis in mice

    PMID:7596437 PMID:8846781

    Open questions at the time
    • Did not define the molecular signaling defect underlying vascular rupture
    • No biochemical mechanism for survival function
  2. 1999 High

    Distinguished TIE1 from TIE2 by showing both are needed in late-organogenesis microvasculature but with non-redundant, tissue-distinct requirements, with TEK specifically essential in endocardium.

    Evidence TEK/TIE double-knockout and mosaic analysis in mice

    PMID:10498691

    Open questions at the time
    • Did not resolve whether TIE1 acts through TIE2 or independently
    • No molecular partners identified
  3. 2000 High

    Resolved the long-standing question of TIE1 signaling competence by showing it has negligible kinase activity and instead forms a constitutive intracellular-domain heterocomplex with TIE2, reframing TIE1 as a modulator rather than autonomous receptor.

    Evidence Co-IP of endogenous receptors and chimeric TrkA/Tie receptor phosphorylation assays

    PMID:10995770

    Open questions at the time
    • Did not identify ectodomain interaction interface
    • Direction of modulation (positive vs negative) unresolved
  4. 2002 High

    Demonstrated that when artificially activated, TIE1 can couple to PI3K/Akt to inhibit apoptosis, mapping Tyr1113 as the PI3K docking site and providing a survival-signaling output.

    Evidence In vitro kinase assay, chimeric c-fms-Tie1 receptor in NIH 3T3, Y1113F mutagenesis, PI3K inhibition

    PMID:11865050

    Open questions at the time
    • Used a chimeric receptor rather than physiological ligand
    • Relevance to endogenous TIE1 with low kinase activity unclear
  5. 2005 High

    Showed that angiopoietin-induced TIE1 phosphorylation is amplified through heteromeric TIE2, establishing that TIE2 trans-phosphorylates kinase-inactive TIE1 in a ligand-dependent manner.

    Evidence Phosphorylation assays with multiple angiopoietins, kinase-inactive TIE1 plus wild-type TIE2 co-transfection

    PMID:15851516

    Open questions at the time
    • Functional consequence of TIE1 phosphorylation not defined
    • Did not address ectodomain regulation
  6. 2007 High

    Defined TIE1 ectodomain as a brake on TIE2: regulated intramembrane proteolysis (ectodomain cleavage then γ-secretase/proteasome processing), stimulated by VEGF and phorbol ester, removes TIE1's restriction of ligand access and enhances TIE2 activation.

    Evidence Biochemical fractionation, γ-secretase/proteasome inhibitors, siRNA, Tie2 phosphorylation and ligand-binding assays; plus siRNA/constitutively-active-TIE2 dependence experiments

    PMID:17504972 PMID:17728252

    Open questions at the time
    • Sheddase identity not yet pinned to ADAM17
    • Quantitative stoichiometry of TIE1:TIE2 not defined
  7. 2010 High

    Visualized dynamic, inhibitory TIE1-TIE2 surface complexes in live cells and mapped the ectodomain surfaces required, showing Ang1 versus Ang2 differentially modulate the interaction.

    Evidence Live-cell FRET proximity assay with contact-surface mutagenesis

    PMID:20227369

    Open questions at the time
    • Atomic-resolution interface not yet determined
    • Downstream signaling consequences not fully mapped
  8. 2012 Medium

    Connected TIE1 abundance to angiopoietin output, showing TIE1 expression level dictates Ang2 agonist/antagonist behavior, that VEGF/TNFα selectively control TIE1 versus TIE2 shedding to set the TIE2:TIE1 ratio, and that TIE1 loss drives Slug-dependent EndMT.

    Evidence Co-IP, adenoviral TIE1 overexpression, time-course shedding Western blots, siRNA with EndMT/promoter readouts

    PMID:22235284 PMID:22342979 PMID:22421998

    Open questions at the time
    • Mostly single-lab observations per finding
    • EndMT mechanism downstream of Slug incompletely defined
  9. 2015 High

    Linked TIE1 to angiogenic specialization in vivo, showing it negatively regulates TIE2 surface presentation in tip cells while cooperating with TIE2 in stalk cells, and is required for lymphatic valve specification and collecting vessel development.

    Evidence Conditional endothelial and Nfatc1Cre TIE1 deletion, retinal vascular and lymphatic valve phenotyping

    PMID:25576926 PMID:26344773

    Open questions at the time
    • Molecular switch between tip-cell inhibition and stalk-cell cooperation undefined
    • Valve specification effectors downstream of TIE1 unresolved
  10. 2016 High

    Integrated TIE1 into integrin and trafficking control: ADAM17 was identified as the in vivo TIE1 sheddase in inflammation, β1 integrin was shown to enhance Ang-induced TIE1-TIE2 interaction and TIE2 trafficking, and TIE1/TIE2 were shown to directly associate with integrins to stimulate ERK.

    Evidence Conditional TIE1 knockout, integrin-blocking antibodies, trafficking/FOXO1 assays, endotoxemia model, FRET and purified-protein binding

    PMID:27548530 PMID:27695111

    Open questions at the time
    • FRET/integrin direct-binding study is single-lab Medium evidence
    • Structural basis of TIE-integrin association undefined
  11. 2017 High

    Provided the structural basis for TIE complex assembly, showing Ang1-induced TIE2 dimerization occurs via an intermolecular Fn3 β-sheet, with TIE1 Fn3 domains structurally compatible for heterodimerization by the same mechanism.

    Evidence X-ray crystallography of TIE1/TIE2 Fn3 and Fn2 domains with mutagenesis and phosphorylation validation

    PMID:28396439

    Open questions at the time
    • No full-length receptor or heterodimer structure
    • Conformational coupling to intracellular kinase not resolved
  12. 2019 High

    Identified LECT2 as a functional TIE1 ligand that disrupts TIE1-TIE2 heterodimers to favor TIE2 homodimerization and PPAR signaling, providing the first defined extracellular ligand acting through TIE1.

    Evidence Co-IP/pulldown, LECT2 overexpression and knockout mice, in vitro migration/tube assays, liver fibrosis models

    PMID:31474362

    Open questions at the time
    • Binding site on TIE1 not mapped
    • Generality beyond hepatic/portal vasculature unclear
  13. 2020 High

    Established heparan sulfate glycosaminoglycans as direct TIE1 ligands that promote TIE1-TIE2 heterodimerization and TIE protein stability, with in vivo HS-binding-site mutation suppressing signaling and disrupting retinal vascularization.

    Evidence Direct binding assays, heterodimerization assays, CRISPR-Cas9 in vivo mutagenesis, retinal phenotyping

    PMID:33020664

    Open questions at the time
    • HS structural specificity not fully defined
    • Interplay with protein ligands (LECT2, angiopoietins) not addressed
  14. 2022 High

    Defined a lymphatic TIE1 role upstream of VEGFR3, showing TIE1 (with TIE2) sustains VEGFR3 surface presentation and VEGF-C-induced PI3K/Akt activation via Ang2 autocrine signaling.

    Evidence Conditional LEC TIE1/TIE2 deletion, Ang2-blocking antibody, PI3K inhibition, VEGFR3 flow cytometry, neonatal lymphangiogenesis assays

    PMID:35763346

    Open questions at the time
    • Mechanism of VEGFR3 surface retention by TIE receptors undefined
    • Direct TIE1-VEGFR3 interaction not demonstrated
  15. 2024 High

    Placed mechanical force upstream of TIE1 regulation, showing PIEZO1 activation triggers ADAM17-mediated TIE1 ectodomain shedding, ANGPT2 exocytosis, and TIE/PI3K/AKT signaling with FOXO1 nuclear export in lymphatic endothelium.

    Evidence PIEZO1 activation in LECs, ADAM17 inhibition, shedding/AKT/FOXO1 and ANGPT2 exocytosis assays

    PMID:38747287

    Open questions at the time
    • Link from PIEZO1 calcium flux to ADAM17 activation not mechanistically detailed
    • In vivo physiological context of this network not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TIE1's multiple ligand inputs (angiopoietins, LECT2, heparan sulfate), shedding cues, and integrin associations are integrated to set a precise TIE2:TIE1 signaling output in distinct vascular beds remains unresolved.
  • No unified quantitative model of TIE1:TIE2 stoichiometry control
  • TIE1 intracellular-domain effectors in TIE2-independent lymphatic functions not identified
  • Direct TIE1 ligand-binding sites largely unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
ADAM17ITGA5ITGAVITGB1ITGB3LECT2TEK
Complex memberships
TIE/integrin (α5β1, αVβ3) complexTIE1-TIE2 heterodimer

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Tie1 (TIE) knockout mice develop severe edema, ruptured microvasculature, and die between E13.5-14.5, demonstrating that Tie1 is required cell-autonomously for vascular endothelial cell integrity and survival, particularly during angiogenic capillary growth, but is not essential for vasculogenesis. Targeted gene disruption (homologous recombination) in mice; chimeric animal analysis The EMBO journal High 7596437 8846781
2002 Tie1 activates phosphatidylinositol 3-kinase (PI3K) and Akt to inhibit apoptosis; a chimeric c-fms-Tie1 receptor in NIH 3T3 cells showed ligand-induced Tie1 autophosphorylation, downstream PI3K and Akt activation, and inhibition of UV-induced apoptosis dependent on PI3K. Tyrosine 1113 was identified as an important PI3K binding site by mutagenesis. In vitro kinase assay with recombinant GST-Tie1; chimeric receptor expression in NIH 3T3 cells; active-site mutagenesis (Y1113F); PI3K inhibitor (LY294002); apoptosis assays Molecular and cellular biology High 11865050
2000 Tie1 forms a pre-formed heterotypic complex with Tie2 in endothelial cells, mediated by the intracellular domains of the receptors; Tie1 does not undergo autophosphorylation or phosphorylate cellular proteins upon activation and displays negligible kinase activity, suggesting it modulates Tie2 signaling rather than signaling independently. Co-immunoprecipitation of endogenous receptors; chimeric TrkA/Tie1 and TrkA/Tie2 receptors; phosphorylation assays The Journal of biological chemistry High 10995770
2005 Multiple angiopoietin proteins (COMP-Ang1, native Ang1, Ang4) induce Tie1 phosphorylation in endothelial cells; Tie2 forms heteromeric complexes with Tie1, enhances Tie1 activation, and can phosphorylate a kinase-inactive Tie1 in a ligand-dependent manner, indicating that angiopoietin-induced Tie1 phosphorylation is amplified via Tie2. Phosphorylation assays in endothelial cells and transfected non-endothelial cells; co-transfection with kinase-inactive Tie1 and wild-type Tie2; Western blot The Journal of cell biology High 15851516
2007 Tie1 is a substrate for regulated intramembrane proteolysis: after ectodomain cleavage, the resulting 45-kDa endodomain undergoes gamma-secretase-mediated processing to a 42-kDa fragment that is degraded by the proteasome. This processing is stimulated by phorbol ester and VEGF. Activation of Tie1 ectodomain cleavage increases COMP-Ang1-mediated Tie2 activation and Tie2 ligand binding, indicating that Tie1 extracellular domain limits ligand access to Tie2. Biochemical fractionation; gamma-secretase inhibitors; proteasome inhibitors; siRNA knockdown of Tie1; Tie2 phosphorylation assays; ligand binding assays The Journal of biological chemistry High 17728252
2007 Ang1-induced Tie1 phosphorylation is Tie2-dependent: Ang1 fails to phosphorylate Tie1 when Tie2 is knocked down or kinase-inactive, and constitutively active Tie2 or a Tie2 agonistic antibody phosphorylates Tie1 without Ang1. Tie1 down-regulates Ang1-mediated AKT and MAPK signaling and modulates blood vessel morphogenesis by suppressing Tie2-driven signaling. siRNA knockdown of Tie2; constitutively active Tie2 expression; Tie2 agonistic antibody; kinase-dead Tie2 co-expression; in vitro and in vivo endothelial assays FASEB journal High 17504972
2010 Tie1 and Tie2 form dynamic complexes on the cell surface detected by FRET; Tie1-Tie2 interactions are inhibitory and differentially modulated by Ang1 versus Ang2. Specific molecular surface areas of the ectodomains essential for Tie1-Tie2 recognition were identified. In vivo FRET-based proximity assay in live cells; mutagenesis of receptor-receptor contact surfaces Molecular cell High 20227369
2012 Tie1 deficiency in endothelial cells induces endothelial-mesenchymal transition (EndMT) through Slug-dependent pathway; Erk1/2, Erk5, and Akt cascades control Slug promoter activity induced by Tie1 deficiency. Tie2 knockdown does not produce this effect. siRNA knockdown of Tie1 and Tie2 in human endothelial cells; promoter activity assays; signaling pathway inhibitors EMBO reports Medium 22421998
2012 Tie1 expression level determines whether Ang2 functions as a Tie2 agonist or antagonist: low Tie1 expression in lymphatic endothelial cells (HLECs) correlates with low Tie1-Tie2 hetercomplex formation and allows Ang2 to act as a Tie2 agonist; overexpression of Tie1 in HLECs restores Tie1-Tie2 heterocomplexes and abolishes Ang2-mediated Tie2 activation. Co-immunoprecipitation; adenovirus-mediated overexpression of Tie1; Tie2 phosphorylation assays; endothelial cell functional assays (migration, tube formation, apoptosis) Biochemical and biophysical research communications Medium 22342979
2012 VEGF and TNFα differentially regulate Tie1 and Tie2 ectodomain cleavage in endothelial cells: VEGF and phorbol ester rapidly activate Tie1 cleavage (within minutes) while Tie2 cleavage requires hours; TNFα stimulates Tie1 cleavage and increases cellular Tie2. Elevated Tie2:Tie1 ratio (from Tie1 cleavage or TNFα treatment) is associated with increased Ang1-activated Tie2 phosphorylation. Western blot of ectodomain shedding; time-course experiments with VEGF, PMA, and TNFα; Ang1 stimulation and Tie2 phosphorylation assays in endothelial cells PloS one Medium 22235284
2016 Ang1 and Ang2 binding to Tie2 increases Tie1-Tie2 interactions in a β1 integrin-dependent manner; Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 deletion reduces Tie2 phosphorylation, decreases downstream Akt activation, increases FOXO1 nuclear localization, and prevents ANG1- and ANG2-induced capillary-to-venous remodeling. In acute endotoxemia, Tie1 ectodomain is rapidly cleaved by ADAM17, reducing ANG1 and autocrine ANG2 agonist activity and suppressing Tie2 signaling. Conditional endothelial Tie1 knockout mice; β1 integrin blocking antibodies; Tie2 phosphorylation and trafficking assays; FOXO1 nuclear localization assays; endotoxemia model; patient samples (hantavirus infection) The Journal of clinical investigation High 27548530
2015 Tie1 negatively regulates Tie2 surface presentation in angiogenic tip cells (reducing Tie2 signaling) while cooperating with Tie2 in remodeling stalk cells to sustain Tie2 signaling. Tie1 is expressed during angiogenesis in tip and stalk cells and downregulated in quiescent adult vasculature. Conditional endothelial Tie1 deletion in mice; postnatal retinal vascular assays; flow cytometry; immunofluorescence; Tie2 surface expression quantification Cell reports High 26344773
2017 Crystal structures reveal that Ang1-induced Tie2 dimerization and activation occurs via formation of an intermolecular β-sheet between the membrane-proximal third Fibronectin type III (Fn3) domains of Tie2. The Fn3 domains of Tie1 and Tie2 are structurally similar and compatible with Tie1/Tie2 heterodimerization by the same mechanism. Mutagenesis of key Tie2 Fn3 residues decreased Ang1-induced Tie2 phosphorylation; mutagenesis of Tie1 Fn3 residues increased basal Tie1 phosphorylation. Additional Fn2-Fn2 domain interactions were found essential for Tie2 oligomerization. X-ray crystallography of Tie1 and Tie2 Fn3 and Fn2 domains; mutagenesis of receptor-receptor contact residues; Tie2 phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 28396439
2003 Fluid shear stress rapidly downregulates Tie1 expression in endothelial cells and induces rapid cleavage of Tie1, with the 45-kDa cleaved Tie1 endodomain binding to Tie2. Shear stress transcriptionally suppresses Tie1 via a negative shear stress response element within 250 bp of the promoter. TNFα also suppresses Tie1 promoter activity. Shear stress apparatus; Western blot of Tie1 cleavage; co-immunoprecipitation of Tie1 endodomain with Tie2; promoter-reporter assays; deletion analysis of promoter FASEB journal Medium 14500555
2011 Tie1 heterozygous deletion (Tie1+/-) on an apoE-deficient background reduces atherosclerosis by 35%. Endothelial-specific conditional Tie1 attenuation decreases atherosclerotic lesions dose-dependently. Atheroprotective laminar flow decreases Tie1 expression in vitro. Tie1 attenuation increases eNOS expression, Tie2 phosphorylation, and IkBα expression while decreasing ICAM levels, indicating a proinflammatory role for Tie1 at atherogenic shear stress sites. Tie1+/- and conditional endothelial Tie1 knockout on apoE-/- background; primary aortic endothelial cells; shear stress experiments; Western blot of eNOS, IkBα, ICAM The Journal of clinical investigation High 21383501
2008 Tie2 mediates Ang1 inhibition of endothelial permeability and apoptosis; siRNA knockdown of Tie1 does not affect Ang1 anti-permeability or anti-apoptotic effects, indicating that Tie1 does not transduce these Ang1 signals. siRNA knockdown of Tie1 and Tie2 (>90% suppression); monolayer permeability assays; apoptosis assays in human endothelial cells Microvascular research Medium 18848573
2009 Loss of Tie1 results in lymphatic vascular abnormalities that precede blood vessel defects. Tie1-/- embryos have abnormally patterned lymph sacs at E12.5 without hemorrhage, and Tie1 hypomorphic embryos display similar lymphatic malformations, indicating Tie1 is required for lymphangiogenesis. Tie1 knockout and hypomorphic mouse models; immunohistochemical analysis of lymphatic markers at multiple developmental time points Arteriosclerosis, thrombosis, and vascular biology High 19910638
2010 Tie1 is required for early lymphatic endothelial cell proliferation and subsequent survival. Tie1 hypomorphic mice show increased Prox1-positive LEC production (dilated jugular lymphatic vessels), abnormal lymphatic patterning, and increased LEC apoptosis after mid-gestation, with severity correlating with Tie1 expression level. Tie1 hypomorphic and conditional knockout mice; EdU/BrdU proliferation assays; TUNEL apoptosis assays; immunofluorescence for Prox1, LYVE1 and other LEC markers Development (Cambridge, England) High 20223757
2014 Tie1 intracellular domain is required for lymphatic remodeling and valve formation independent of Tie2; conditional deletion of Tie1-ICD postnatally disrupts collecting vessel formation and lymphatic valvulogenesis, while neonatal deletion of Tie2 does not affect lymphatic vessel growth and maturation. Conditional knockout mice (Tie1-ICD deletion and Tie2 deletion using inducible Cre); analysis of lymphatic vessel morphology and valve formation Arteriosclerosis, thrombosis, and vascular biology High 24764452
2015 Tie1 is required for lymphatic valve specification and collecting vessel development; conditional deletion of Tie1 with Nfatc1Cre causes agenesis of lymphatic valves and deficiency of collecting lymphatic vessels, preventing initiation of valve specification marked by Prox1-high LEC clusters associated with turbulent flow. Conditional Tie1 deletion using Nfatc1Cre; immunofluorescence for Prox1, PECAM, integrin-α9 and other valve markers; postnatal lymphatic analysis Developmental biology High 25576926
2019 LECT2 is a functional ligand of Tie1. LECT2 binding to Tie1 disrupts Tie1-Tie2 heterodimerization, facilitates Tie2-Tie2 homodimerization, activates PPAR signaling, and inhibits endothelial cell migration and tube formation. In vivo, LECT2 overexpression inhibits portal angiogenesis and worsens liver fibrosis, while Lect2 knockout reverses these effects. Co-immunoprecipitation; pulldown assays; LECT2 overexpression and knockout mice; in vitro migration and tube formation assays; adeno-associated viral vector shRNA treatment Cell High 31474362
2016 Tie1 and Tie2 constitutively associate with integrins α5β1 and αVβ3 through their ectodomains on the endothelial surface; this interaction is direct (demonstrated with purified components) and enhanced by fibronectin for Tie2. Cooperative Tie/integrin interactions selectively stimulate ERK/MAPK signaling in the presence of both Ang1 and fibronectin. Live cell FRET-based proximity assay; in vitro binding assays with purified proteins; ERK/MAPK phosphorylation assays; fibronectin and Ang1 co-stimulation PloS one Medium 27695111
2020 Heparan sulfate glycosaminoglycans (HS GAGs) are direct ligands for Tie1 and regulate Ang-Tie signaling: HS-Tie1 interaction promotes Tie1-Tie2 heterodimerization and enhances Tie1 stability. CRISPR-Cas9 mutagenesis abolishing HS-Tie1 binding in vivo decreases Tie protein levels, suppresses pathway signaling, and causes aberrant retinal vascularization. Direct binding assays between HS GAGs and Tie1; Tie1-Tie2 heterodimerization assays; CRISPR-Cas9 mutagenesis of HS binding site in vivo; retinal vascularization phenotyping Nature chemical biology High 33020664
2022 Tie1 in lymphatic endothelial cells is required for VEGF-C-induced full Akt activation downstream of PI3K; neonatal deletion of Tie1 (or Tie2) in LECs decreases VEGFR3 surface presentation and inhibits lymphangiogenesis. Ang2 secretion from LECs (induced by VEGF-C) signals via Tie receptors to regulate VEGFR3 cell-surface expression. Conditional Tie1 and Tie2 gene deletion in LECs; Ang2-blocking antibodies; PI3K inhibitors; VEGFR3 surface expression flow cytometry; lymphangiogenesis assays in neonatal and adult mice The Journal of clinical investigation High 35763346
2024 PIEZO1 activation in lymphatic endothelial cells (LECs) causes rapid ectodomain shedding of Tie1 by ADAM17, concurrent exocytosis of ANGPT2, and increased TIE/PI3K/AKT signaling followed by nuclear export of FOXO1; this establishes a functional network placing PIEZO1 upstream of TIE1 ectodomain shedding in lymphatic signaling. PIEZO1 activation in LECs; ADAM17 inhibitor studies; Western blot of Tie1 shedding; AKT and FOXO1 phosphorylation/localization assays; ANGPT2 exocytosis assays The Journal of clinical investigation High 38747287
2008 Overexpression of Tie1 in endothelial cells induces tyrosine phosphorylation of Tie1 and upregulates adhesion molecules VCAM-1, E-selectin, and ICAM-1 through a p38-dependent mechanism, enhancing monocyte attachment to endothelial cells. Tie1 overexpression in human aortic endothelial cells and HUVECs; Western blot and flow cytometry for adhesion molecules; p38 inhibitor; monocyte adhesion assays Biochemical and biophysical research communications Medium 18448073
1999 Genetic analysis of TEK/TIE double-knockout embryos shows that vasculogenesis proceeds normally without both receptors, but TEK is absolutely required in the endocardium at E10.5. Both TEK and TIE are required in the microvasculature during late organogenesis, demonstrating essential but non-redundant roles in maintaining vascular integrity with distinct tissue requirements. TEK/TIE double knockout mice; mosaic (chimeric) analysis to determine cell-autonomous requirements Development (Cambridge, England) High 10498691
2021 Tie receptor signaling (detected by phosphorylation preferentially in the central vein area) acts as a selective regulator of vascular Wnt activity in liver endothelium, orchestrating angiocrine signaling and controlling hepatocyte function during liver regeneration. Spatial cell sorting combined with transcriptomics and quantitative phosphoproteomics; biological validation of Tie receptor-Wnt signaling axis in liver regeneration Developmental cell Medium 34038707
2021 m6A methylation of TIE1 mRNA 3'UTR by METTL14 increases TIE1 mRNA stability; miR-4729 targets METTL14 3'UTR to suppress METTL14 expression, reducing global m6A modification and TIE1 mRNA methylation at a specific 3'UTR site, thereby decreasing TIE1 expression and the TIE1/VEGFA signaling loop in endothelial cells. RNA immunoprecipitation-PCR for m6A sites; luciferase reporter assay; miR-4729 overexpression; Western blot; tube formation and migration assays Annals of translational medicine Medium 33708859

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 1466 7596437
2009 Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nature reviews. Molecular cell biology 1128 19234476
2017 Therapeutic targeting of the angiopoietin-TIE pathway. Nature reviews. Drug discovery 493 28529319
1995 The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. The EMBO journal 398 8846781
2012 Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM). Biochimica et biophysica acta 376 22575682
2005 Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Experimental cell research 254 16225862
2007 Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. Journal of immunology (Baltimore, Md. : 1950) 248 17513791
2003 Role of Angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell and tissue research 219 12915980
2012 The complex role of angiopoietin-2 in the angiopoietin-tie signaling pathway. Cold Spring Harbor perspectives in medicine 216 22951441
2016 Tie1 controls angiopoietin function in vascular remodeling and inflammation. The Journal of clinical investigation 211 27548530
2019 LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis. Cell 184 31474362
2000 Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. The American journal of pathology 176 11073808
2009 Autocrine and paracrine angiopoietin 1/Tie-2 signaling promotes muscle satellite cell self-renewal. Cell stem cell 175 19733541
2005 Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. The Journal of cell biology 163 15851516
2017 Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems. Clinical science (London, England : 1979) 160 27941161
1998 TIE1 and TIE2 receptor tyrosine kinases inversely regulate embryonic angiogenesis by the mechanism of intussusceptive microvascular growth. Microvascular research 158 9683559
2003 Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma. Hepatology (Baltimore, Md.) 155 12717391
2010 Tie1-Tie2 interactions mediate functional differences between angiopoietin ligands. Molecular cell 137 20227369
2015 The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells. Cell reports 133 26344773
2009 A noncoding antisense RNA in tie-1 locus regulates tie-1 function in vivo. Blood 132 19880500
2007 Angiopoietin: a TIE(d) balance in tumor angiogenesis. Molecular cancer research : MCR 127 17634421
2001 Tie-1-directed expression of Cre recombinase in endothelial cells of embryoid bodies and transgenic mice. Journal of cell science 126 11171372
2000 Expression of Tie1, Tie2, and angiopoietins 1, 2, and 4 in Kaposi's sarcoma and cutaneous angiosarcoma. The American journal of pathology 123 10854238
1994 The mouse tie receptor tyrosine kinase gene: expression during embryonic angiogenesis. Oncogene 119 7507228
2000 VEGF, its receptors and the tie receptors in recurrent miscarriage. Molecular human reproduction 117 10694277
2000 Induction of angiopoietin and Tie receptor mRNA expression after cerebral ischemia-reperfusion. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 116 10698077
2001 Angiopoietin and Tie signaling pathways in vascular development. Matrix biology : journal of the International Society for Matrix Biology 115 11566266
1999 Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development. Development (Cambridge, England) 112 10498691
2006 Localization of Ang-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Laboratory investigation; a journal of technical methods and pathology 110 16969369
2018 Endothelial Activation: The Ang/Tie Axis in Sepsis. Frontiers in immunology 108 29740443
2006 Breaking up the tie: disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion. Pharmacology & therapeutics 103 16626807
2001 Sinusoidal endothelial cell proliferation and expression of angiopoietin/Tie family in regenerating rat liver. Journal of hepatology 103 11434615
2007 Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. The Journal of biological chemistry 96 17728252
2021 Faricimab: an investigational agent targeting the Tie-2/angiopoietin pathway and VEGF-A for the treatment of retinal diseases. Expert opinion on investigational drugs 93 33471572
2021 A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie-Wnt signaling axis in the liver. Developmental cell 87 34038707
2013 Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence 86 23652985
2007 Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 86 17504972
2002 The endothelial receptor tyrosine kinase Tie1 activates phosphatidylinositol 3-kinase and Akt to inhibit apoptosis. Molecular and cellular biology 86 11865050
2002 Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue. Arthritis research 85 12010571
2021 THE ANGIOPOIETIN/TIE PATHWAY IN RETINAL VASCULAR DISEASES: A Review. Retina (Philadelphia, Pa.) 84 33136975
2019 Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease. Expert opinion on investigational drugs 83 31513439
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2022 Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression. The Journal of clinical investigation 80 35763346
2018 Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis. The Journal of clinical investigation 80 29355844
2017 Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization. Proceedings of the National Academy of Sciences of the United States of America 78 28396439
2000 Tie-2 and angiopoietin-2 expression at the fetal-maternal interface: a receptor ligand model for vascular remodelling. Molecular human reproduction 78 10611265
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2004 Transcriptional coregulator SNW/SKIP: the concealed tie of dissimilar pathways. Cellular and molecular life sciences : CMLS 71 15052407
2011 Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stress-specific manner. The Journal of clinical investigation 64 21383501
2000 Evidence for heterotypic interaction between the receptor tyrosine kinases TIE-1 and TIE-2. The Journal of biological chemistry 64 10995770
2014 Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy. The Journal of clinical investigation 62 24430181
2009 Loss of endothelial Tie1 receptor impairs lymphatic vessel development-brief report. Arteriosclerosis, thrombosis, and vascular biology 62 19910638
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2001 Differential expression of Tie-2 receptors and angiopoietins in response to in vivo hypoxia in rats. American journal of physiology. Lung cellular and molecular physiology 56 11504684
2010 Abnormal embryonic lymphatic vessel development in Tie1 hypomorphic mice. Development (Cambridge, England) 55 20223757
2006 Emerging roles of the Angiopoietin-Tie and the ephrin-Eph systems as regulators of cell trafficking. Journal of leukocyte biology 55 16864601
1997 Analysis of Tie receptor tyrosine kinase in haemopoietic progenitor and leukaemia cells. British journal of haematology 53 9233584
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2012 Tie1 deficiency induces endothelial-mesenchymal transition. EMBO reports 47 22421998
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2014 Genetic dissection of tie pathway in mouse lymphatic maturation and valve development. Arteriosclerosis, thrombosis, and vascular biology 45 24764452
2017 TIE-2 expressing monocytes in human cancers. Oncoimmunology 44 28507810
2014 Ring the BELL and tie the KNOX: roles for TALEs in gynoecium development. Frontiers in plant science 42 24688486
2013 Expression and function of Angiopoietins and their tie receptors in human basophils and mast cells. Journal of biological regulators and homeostatic agents 42 24152847
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2004 Expression and function of the angiopoietin receptor Tie-2 in human eosinophils. The Journal of allergy and clinical immunology 38 15536413
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2001 Expression and potential role of angiopoietins and Tie-2 in early development of the mouse metanephros. Developmental dynamics : an official publication of the American Association of Anatomists 36 11507774
2013 TIE-2 and VEGFR kinase activities drive immunosuppressive function of TIE-2-expressing monocytes in human breast tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 35 23649001
2004 Alterations in expression of angiopoietins and the Tie-2 receptor in the retina of streptozotocin induced diabetic rats. Molecular vision 35 15354084
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2011 Myoferlin gene silencing decreases Tie-2 expression in vitro and angiogenesis in vivo. Vascular pharmacology 29 21586340
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2012 Tie1 regulates the Tie2 agonistic role of angiopoietin-2 in human lymphatic endothelial cells. Biochemical and biophysical research communications 26 22342979
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2008 Receptor tyrosine kinase Tie-1 overexpression in endothelial cells upregulates adhesion molecules. Biochemical and biophysical research communications 24 18448073
2024 The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development. The Journal of clinical investigation 23 38747287
2008 Roles of the receptor tyrosine kinases Tie1 and Tie2 in mediating the effects of angiopoietin-1 on endothelial permeability and apoptosis. Microvascular research 22 18848573
2005 Cellular life histories and bow tie biology. American journal of human biology : the official journal of the Human Biology Council 22 15611965
2004 Differential expression of the Tie-2 receptor and its ligands in human pancreatic tumors. Journal of the American College of Surgeons 22 15501112
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2012 Circulating angiopoietin and Tie-2 levels in systemic sclerosis. Rheumatology international 21 22461185
2005 Spatial and temporal distribution of Tie-1 and Tie-2 during very early development of the human placenta. Placenta 21 16026828

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