Affinage

TEK

Angiopoietin-1 receptor · UniProt Q02763

Length
1124 aa
Mass
125.8 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TEK/TIE2 is an endothelial receptor tyrosine kinase that governs vascular quiescence, maintenance, and angiogenic remodeling, and is also functionally expressed in pericytes and aortic fibroblasts (PMID:10498691, PMID:18425120, PMID:28719590, PMID:37476204). The ligand angiopoietin-1 must assemble into at least tetrameric, disulfide-linked multimers to bind and activate TIE2 (PMID:15769741), engaging the receptor at the tip of an arrowhead-shaped ectodomain built from three Ig and three EGF domains through a lock-and-key interaction (PMID:16732286); ligand-driven dimerization is executed by intermolecular β-sheet formation between membrane-proximal fibronectin type III (Fn3) domains, while Fn2–Fn2 contacts maintain preformed receptor oligomers (PMID:28396439, PMID:28396397). Activated TIE2 autophosphorylates C-terminal tyrosines that nucleate a multifunctional docking complex: Tyr1100 recruits Grb2, Grb7, Grb14, Shp2 (PTPN11), and the p85 subunit of PI3K (PMID:7478529, PMID:10521483), and Tyr1106 binds the adaptor Dok-R to couple the receptor to migration signaling (PMID:9764820, PMID:12665569). These inputs drive PI3K/Akt and Erk arms that are spatially partitioned—trans-TIE2 complexes bridged by Ang1 at cell-cell junctions favor Akt and quiescence, whereas ECM-anchored TIE2 at cell-substratum contacts favors Erk and angiogenesis (PMID:18425120). Downstream, Akt sustains venous endothelial identity by proteasomal stabilization of COUP-TFII and restrains FOXO1 to enforce vascular stability and atheroprotection (PMID:28005008, PMID:37476204). Angiopoietin-2 is a context-dependent partial agonist/antagonist whose switch is gated by Tie1 ectodomain shedding during inflammation (PMID:16895971, PMID:27548529), and in TIE2-low angiogenic endothelium ANG2 instead signals through integrins to activate FAK and RAC1 independently of TIE2 (PMID:22585576). TIE2 activity is negatively set by the phosphatase VE-PTP (PTPRB), pharmacologic inhibition of which boosts TIE2/Akt/eNOS/Erk signaling and is protective in ocular neovascularization and ischemic kidney injury (PMID:25180601, PMID:36787763), and by EphA4-mediated suppression of Akt (PMID:31689239); receptor levels are further controlled by GATA3/laminar-flow-driven transcription and MMP14 ectodomain shedding in sepsis (PMID:29979219). TIE2 signaling is essential in vivo for endocardial integrity and trabeculation, microvascular maintenance, renal vasa recta formation, and Schlemm's canal development (PMID:10498691, PMID:31112136, PMID:29237738, PMID:27270174). Gain-of-function somatic mutations such as L914F cause ligand-independent hyperphosphorylation and chronic MAPK activation underlying venous malformations (PMID:19079259, PMID:26319232), whereas loss-of-function TEK alleles cause primary congenital glaucoma through haploinsufficiency of angiopoietin-TEK signaling in anterior chamber vascular development (PMID:27270174).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 Medium

    Established that the TIE2 cytoplasmic tail signals through specific phosphotyrosine-dependent SH2 adaptors, defining its earliest signaling partners.

    Evidence Soluble TEK kinase domain library screen and endothelial lysate pulldown with C-tail tyrosine mutagenesis

    PMID:7478529

    Open questions at the time
    • PI3K and PLCγ not detected here, conflicting with later docking studies
    • in vitro kinase-domain assay rather than full-length receptor in cells
  2. 1997 Medium

    Showed TIE2 is actively phosphorylated in both angiogenic and quiescent adult vessels, framing its dual role in remodeling and maintenance.

    Evidence Tie2 IP/anti-phosphotyrosine blotting across rat/mouse tissues with RPA and IHC

    PMID:9314838

    Open questions at the time
    • does not resolve which ligand or downstream pathway drives quiescence vs. angiogenesis
  3. 1998 Medium

    Identified the Dok-R adaptor and an endothelial-selective promoter, linking TIE2 to RasGAP/Nck/Crk effectors and explaining endothelial-restricted expression.

    Evidence Yeast two-hybrid and co-IP for Dok-R; reporter/EMSA dissection of the Tie2 promoter

    PMID:9461528 PMID:9764820

    Open questions at the time
    • functional consequence of Dok-R/Crk/Nck assembly not yet tied to a phenotype
    • transcription factors binding promoter element U unidentified
  4. 1999 High

    Defined the Tyr1100 multifunctional docking site and demonstrated in vivo that TEK is cell-autonomously required for endocardial integrity and microvascular maintenance.

    Evidence Ang1-stimulated co-IP/mutagenesis of Tyr1100 with survival/migration assays; double-KO and chimeric mouse genetics

    PMID:10498691 PMID:10521483

    Open questions at the time
    • spatial regulation of Akt vs. Erk outputs not yet addressed
    • redundancy with TIE not fully mechanistically resolved
  5. 2003 High

    Pinpointed Tyr1106 as the autophosphorylation site coupling TIE2 to Dok-R-driven endothelial migration, separating migration from survival signaling.

    Evidence Phospho-specific antibody, mutagenesis, and migration rescue in Tie2-null endothelial cells

    PMID:12665569

    Open questions at the time
    • in vivo requirement of Tyr1106 not tested
    • interplay with Tyr1100 docking complex unclear
  6. 2005 High

    Resolved Ang1 multimerization requirements and the autocrine destabilizing action of Ang2, clarifying ligand-level control of receptor activation.

    Evidence Defined Ang variants with EM/SDS-PAGE and phosphorylation assays; 3D spheroid and explant models with soluble Tie2 blockade

    PMID:15687104 PMID:15769741

    Open questions at the time
    • structural basis of how multimerization clusters receptors not yet defined
    • autocrine vs. paracrine Ang2 receptor topology unresolved
  7. 2006 High

    Provided the atomic structure of the TIE2 ectodomain and defined Ang2 as a weak partial agonist whose binding triggers receptor internalization.

    Evidence X-ray crystallography of Tie2/Ang2 with structure-based mutagenesis; concentration-response phosphorylation and internalization assays

    PMID:16732286 PMID:16895971

    Open questions at the time
    • lock-and-key binding with minimal conformational change does not explain how activation signal is transmitted
    • molecular trigger distinguishing Ang1 vs Ang2 agonism unresolved
  8. 2008 High

    Established spatial signal partitioning (trans-junctional Akt vs. ECM-anchored Erk), pericyte TIE2 function, and the somatic gain-of-function basis of venous malformations.

    Evidence TIE2 localization imaging with Akt/Erk readouts and transcriptomics; pericyte assays with antisense; lesion sequencing and mutant phosphorylation/localization assays

    PMID:18425120 PMID:18436850 PMID:19079259

    Open questions at the time
    • mechanism converting receptor location to differential effector choice not molecularly defined
    • L914F abnormal localization mechanism unresolved
  9. 2012 High

    Revealed a TIE2-independent ANG2-integrin axis in TIE2-low angiogenic endothelium, expanding angiopoietin signaling beyond the receptor.

    Evidence Integrin binding/co-IP, FAK phosphorylation, RAC1 activity assays, and in vivo ANG2 neutralization in tumor vasculature

    PMID:22585576

    Open questions at the time
    • which integrin heterodimers mediate binding not fully specified
    • relationship to TIE2-dependent ANG2 effects in same vascular bed unclear
  10. 2015 High

    Defined the cellular pathology of VM-causing TIE2 mutations: trafficking defects, chronic MAPK activation, fibronectin ECM loss, and plasmin pathway upregulation.

    Evidence Panel of 22 TIE2 mutants in endothelial cells, mouse models, patient biopsy ultrastructure, and ECM/MAPK assays

    PMID:26319232

    Open questions at the time
    • link between specific trafficking defects and downstream MAPK level not quantified per mutant
  11. 2014 High

    Identified VE-PTP (PTPRB) as the negative regulator dephosphorylating TIE2, providing a druggable node to activate the pathway even under high ANG2.

    Evidence VE-PTP antibody and small-molecule inhibitor AKB-9778 with TIE2/AKT/eNOS/ERK readouts and ocular vascular mouse models

    PMID:25180601

    Open questions at the time
    • direct enzyme-substrate kinetics on specific TIE2 phosphosites not resolved
  12. 2016 High

    Established the Tie1-gated ANG2 agonist/antagonist switch, the Akt/COUP-TFII venous identity axis, and the TEK haploinsufficiency mechanism of primary congenital glaucoma.

    Evidence Infection vs. pathogen-free mouse models with FOXO1/Tie1-cleavage readouts; Tek deletion with PI3K/proteasome inhibition and COUP-TFII blots; functional characterization of PCG TEK variants with hemizygous mouse IOP

    PMID:27270174 PMID:27548529 PMID:28005008

    Open questions at the time
    • protease responsible for Tie1 shedding in inflammation not pinned down here
    • dose threshold for Schlemm's canal phenotype not defined
  13. 2017 High

    Defined the structural mechanism of receptor dimerization (Fn3 β-sheet) and preformed oligomerization (Fn2–Fn2), established pericyte TIE2 signaling via Calpain/Akt/FOXO3A, and roles in renal vasa recta development.

    Evidence Crystal structures of Tie2/Tie1 Fn domains with interface mutagenesis; pericyte siRNA and Ng2-Cre deletion with signaling readouts; conditional Tie2 and Ang1/Ang2 KO renal phenotyping

    PMID:28396397 PMID:28396439 PMID:28719590 PMID:29237738

    Open questions at the time
    • how Ang1 cross-links dimers into higher-order clusters remains a model, not directly observed
    • pericyte vs. endothelial TIE2 division of labor in vivo incompletely defined
  14. 2018 High

    Showed TIE2 levels are suppressed in sepsis at two levels—MMP14 ectodomain shedding and loss of laminar-flow/GATA3-driven transcription—linking hemodynamics and inflammation to receptor abundance.

    Evidence TNF-α HUVEC assays, cecal ligation/puncture mice, MMP14 and GATA3 manipulation, shear flow, and septic human kidney biopsies

    PMID:29979219

    Open questions at the time
    • relative contribution of shedding vs. transcriptional loss to vascular leak not quantified
  15. 2019 High

    Defined endocardial TIE2 control of trabeculation via a Bmp10/retinoic-acid/Erk axis, with pharmacologic RA inhibition partially rescuing the phenotype.

    Evidence Endocardial-specific Tie2 conditional KO with proliferation, Bmp10/RA analysis, and in utero RA antagonist treatment

    PMID:31112136

    Open questions at the time
    • how endocardial TIE2 loss non-cell-autonomously raises Bmp10/RA in myocardium not fully mechanistic
  16. 2020 High

    Identified EphA4 and SVEP1 as additional regulators—EphA4 suppresses TIE2/Akt in stroke remodeling, and SVEP1 transcriptionally drives TEK expression relevant to PCG penetrance.

    Evidence Endothelial EphA4 KO and peptide inhibition with p-Akt readout; SVEP1 stimulation of HUVECs with qPCR and PCG variant comparison

    PMID:31689239 PMID:33027505

    Open questions at the time
    • direct biochemical EphA4-TIE2 interaction not shown
    • SVEP1 effect characterized only at transcriptional level
  17. 2021 Medium

    Defined epigenetic control of TEK transcription by SIRT7/EST-1-mediated H3K18 deacetylation at the promoter.

    Evidence ChIP-qPCR, EMSA, reporter assay, Co-IP, and siRNA knockdown

    PMID:34797559

    Open questions at the time
    • single-lab mechanism; physiological context of SIRT7 repression of TEK not established in vivo
  18. 2023 High

    Extended VE-PTP/TIE2/FOXO1 biology to disease, showing TIE2 activation protects ischemic kidneys and that endothelial TIE2 is atheroprotective via FOXO1 restraint.

    Evidence VE-PTP conditional KO and Hepta-ANG1 in IR-AKI with scRNAseq; arterial endothelial Tie2 deletion in atherosclerosis with FOXO1/adhesion readouts

    PMID:36787763 PMID:37476204

    Open questions at the time
    • how TIE2/Akt mechanistically excludes FOXO1 from the nucleus in these tissues not resolved
    • fibroblast TIE2 function only partially characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How spatially distinct TIE2 complexes are molecularly decoded into Akt vs. Erk outputs, and how higher-order Ang1-driven clustering is physically organized at junctions vs. matrix, remain unresolved.
  • no structural model of the active full-length clustered receptor
  • the switch coupling localization to effector selection is undefined
  • in vivo phosphosite-resolved signaling maps lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1500931 Cell-Cell communication 2
Partners
ANGPT1ANGPT2DOK4GRB14GRB2GRB7PTPN11PTPRB

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The autophosphorylated TEK/TIE2 kinase domain associates with GRB2 and SH-PTP2 (PTPN11) from endothelial cell lysates in a manner highly dependent on specific tyrosine residues in the TEK C-tail; PI3-kinase and PLCγ were NOT detected as binding partners in this assay. Radiolabeled soluble TEK kinase domain used to probe mouse embryo expression library and pull down from endothelial lysates; site-directed mutagenesis of C-tail tyrosines Oncogene Medium 7478529
1997 Tie2 protein is tyrosine-phosphorylated (actively signaling) in endothelial cells of both angiogenic tissues (healing wounds, ovary, uterus) and quiescent adult vasculature, indicating dual roles in angiogenesis and vascular maintenance. Immunoprecipitation of Tie2 from rat/mouse tissues followed by anti-phosphotyrosine blotting; RNase protection assay for mRNA; immunohistochemistry Circulation research Medium 9314838
1998 TEK/Tie2 signals through a novel docking protein Dok-R (now DOKR/DOK4): activated TEK phosphorylates Dok-R via a PTB domain interaction; phosphorylated Dok-R co-immunoprecipitates rasGAP and Nck, and Dok-R is constitutively bound to Crk through its proline-rich tail. Yeast two-hybrid screen with activated Tek; co-immunoprecipitation; co-expression in cells; domain-mapping Oncogene Medium 9764820
1998 The murine Tie2/Tek proximal promoter drives endothelial cell-specific transcription through two positive regulatory elements (U and A) and one inhibitory region (I); element U functions in an endothelial-cell-selective manner and binds distinct protein factors. Reporter transfection experiments in endothelial vs. non-endothelial cells; electrophoretic mobility-shift assays (EMSA); deletion mutagenesis The Biochemical journal Medium 9461528
1999 Angiopoietin-1 stimulation of TEK recruits five SH2-domain proteins (Grb2, Grb7, Grb14, Shp2, and p85 of PI3K) to a multifunctional docking site at Tyr1100 in the Tek C-tail; mutation of Tyr1100 abolishes Grb2/Grb7 binding and p85/Grb7 phosphorylation in vivo; Ang1-induced Tek signaling activates both cell survival (PI3K-dependent) and migration pathways. Yeast two-hybrid; in vivo co-immunoprecipitation; site-directed mutagenesis of Tyr1100; cell migration and survival assays with PI3K inhibitors The Journal of biological chemistry High 10521483
1999 Genetic ablation of both TEK and TIE in mice demonstrates that TEK is absolutely required cell-autonomously for endocardial integrity at E10.5, whereas TEK and TIE are dispensable for initial vasculogenesis but redundantly required for microvasculature maintenance during late organogenesis and in the adult. Double-knockout mouse genetics; mosaic analysis in chimeric embryos Development (Cambridge, England) High 10498691
2003 Tyr1106 on Tie2 is an Ang1-dependent autophosphorylation site that mediates binding and phosphorylation of Dok-R via its PTB domain; the Dok-R PH domain further contributes to Tie2 binding in a PI3K-dependent manner; Tie2 mutant lacking Tyr1106 fails to restore endothelial cell migration in Tie2-null cells, establishing Tyr1106 as critical for coupling cell migration signaling to Ang1. Site-directed mutagenesis; phosphorylation state-specific antibody; co-immunoprecipitation; migration rescue assay in Tie2-null endothelial cells Molecular and cellular biology High 12665569
2005 Angiopoietin-2 acts as a rapidly acting autocrine destabilizer of quiescent endothelium via Tie2; exogenous Ang1, soluble Tie2, and VEGF rescue Ang2-induced endothelial detachment, but soluble Tie2 cannot block autocrine (endogenous) Ang2-mediated detachment, demonstrating an internal autocrine loop mechanism distinct from paracrine Ang2 signaling. 3D endothelial/smooth-muscle co-culture spheroid model; umbilical-vein explant model; Tie2 small-molecule inhibitor; soluble Tie2 blocking; overexpression and stimulated release of Ang2 Journal of cell science High 15687104
2005 Ang1 oligomerization state is critical for Tie2 binding and activation: at least tetrameric (≥4 subunit) multimers mediated by intermolecular disulfide bonds involving Cys41 and Cys54 are required; dimeric and monomeric Ang1 variants lose binding and activation capacity for Tie2. Generation of Ang1/Ang2 variants; SDS-PAGE; rotary metal-shadowing transmission electron microscopy; Tie2 phosphorylation assays; binding assays The Journal of biological chemistry High 15769741
2006 Crystal structures of the Tie2 receptor ectodomain (alone and in complex with Ang2) reveal that Tie2 contains three (not two) Ig domains folded with three EGF domains into an arrowhead shape; Ang2 binds at the tip via a lock-and-key mechanism with minimal conformational change in either molecule, similar to antibody-antigen recognition; structure-based mutagenesis validated the binding interface. X-ray crystallography; structure-based mutagenesis Nature structural & molecular biology High 16732286
2006 Activation of Tie2 by either Ang1 or Ang2 leads to ligand release from the endothelial cell surface and receptor internalization/degradation; Ang2 is a considerably weaker Tie2 activator than Ang1 and behaves as a partial agonist; Ang1-induced internalization is faster and more pronounced than Ang2-induced internalization. Concentration-response phosphorylation assays; receptor internalization assays; ligand binding and accumulation assays in endothelial cells Journal of cell science Medium 16895971
2008 Ang1 bridges Tie2 molecules at cell-cell contacts to form trans-Tie2 complexes, preferentially activating Akt; in isolated cells, ECM-bound Ang1 anchors Tie2 at cell-substratum contacts, preferentially activating Erk; these spatially distinct Tie2 complexes produce differential downstream gene expression profiles linked to vascular quiescence vs. angiogenesis respectively. Fluorescence microscopy of Tie2 localization; Akt and Erk phosphorylation assays; microarray gene expression with real-time PCR validation; endothelial cell-cell contact manipulation Nature cell biology High 18425120
2008 Somatic TEK mutations (including the frequent L914F substitution and several double mutations in cis) cause ligand-independent TIE2 hyperphosphorylation in vitro; the L914F mutant shows abnormal subcellular localization and retains ligand responsiveness, in contrast to the inherited R849W mutant, indicating mechanistically distinct pathogenic pathways for inherited vs. sporadic venous malformations. Sequencing of lesion vs. blood DNA; in vitro TIE2 phosphorylation assays; overexpression of mutant TIE2 in HUVECs with immunofluorescence localization Nature genetics High 19079259
2008 Pericytes express a functionally active Tie2 receptor; Ang1 promotes pericyte survival and migration via Tie2, and Ang2 increases pericyte apoptosis; Tie2 antisense confirmed angiopoietin effects are Tie2-dependent in pericytes. ELISA, Western blot, flow cytometry for Tie2 on pericytes; apoptosis assays (Annexin V); migration assay; Tie2 antisense knockdown Investigative ophthalmology & visual science Medium 18436850
2012 ANG-2 binds integrins (not Tie2) on TIE2-low angiogenic endothelial cells, inducing FAK phosphorylation (integrin adaptor), RAC1 activation, migration, and sprouting angiogenesis in a TIE2-independent manner; in vivo ANG-2 blockade inhibits FAK phosphorylation in TIE2-low ECs. Identification of TIE2-low subpopulation in tumor vasculature; co-IP/binding assays of ANG-2 with integrins; phosphorylation assays for FAK; RAC1 activity assay; in vivo ANG-2 neutralization The Journal of clinical investigation High 22585576
2014 VE-PTP (PTPRB) negatively regulates TIE2 by dephosphorylation; inhibition of VE-PTP catalytic activity with AKB-9778 activates TIE2, enhances Ang1-induced TIE2 activation, and stimulates phosphorylation of AKT, eNOS, and ERK in the TIE2 pathway; this is effective even in the presence of high ANG2. Anti-VE-PTP antibody and small-molecule VE-PTP inhibitor (AKB-9778); TIE2 and downstream signaling phosphorylation assays; mouse models of ocular NV and vascular leakage The Journal of clinical investigation High 25180601
2015 Analysis of 22 TIE2 patient mutations reveals that VM-causing mutations cause defective receptor trafficking and subcellular localization by multiple distinct mechanisms, leading to attenuated ligand response; TIE2 mutations cause chronic MAPK pathway activation, loss of endothelial monolayer integrity due to fibronectin ECM deficiency, and upregulation of the plasminogen/plasmin proteolytic pathway. Endothelial cell cultures with 22 TIE2 mutants; mouse models; ultrastructural analysis of patient biopsies; Western blotting for MAPK; ECM fibronectin quantification Human molecular genetics High 26319232
2016 TEK mutations in primary congenital glaucoma (PCG) cause haploinsufficiency through multiple protein loss-of-function mechanisms including absence of protein production, aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced ligand responsiveness; hemizygosity for Tek in mice leads to hypomorphic Schlemm's canal and elevated intraocular pressure, demonstrating dose-sensitivity of angiopoietin-TEK signaling in anterior chamber vascular development. Cellular assays in transfected cells for each TEK variant; immunofluorescence for localization; proteasome inhibition assays; mouse hemizygous Tek model with IOP measurement The Journal of clinical investigation High 27270174
2016 ANG2 acts as a Tie2 antagonist during infection/inflammation (when Tie1 is cleaved by ectodomain shedding), suppressing p-Tie2, activating FOXO1, increasing ANG2 expression (positive feedback), and promoting vascular leakage; under pathogen-free conditions, ANG2 acts as a Tie2 agonist promoting high p-Tie2, low FOXO1, and stable vessel enlargement. Tie1 ectodomain cleavage (induced by infection or TNF-α) switches ANG2 from agonist to antagonist. Mouse models of Mycoplasma pulmonis infection vs. pathogen-free conditions; anti-Tie2 antibody; PI3K inhibition; ANG2 overexpression/neutralization; ANG1 administration; FOXO1 activity measurement; Tie1 cleavage analysis The Journal of clinical investigation High 27548529
2016 Tie2 insufficiency in endothelial cells decreases COUP-TFII protein levels (a key venous identity regulator); Ang1 stimulation increases COUP-TFII in cultured ECs; Tie2 knockdown or blockade of the downstream PI3K/Akt pathway reduces COUP-TFII, which can be reversed by proteasome inhibition, establishing that Tie2 maintains venous EC identity via Akt-mediated proteasomal stabilization of COUP-TFII. Endothelial-specific Tek deletion in mice (Tie2-Cre); Ang1 stimulation of cultured ECs; PI3K/Akt inhibition; proteasome inhibition; Western blot for COUP-TFII eLife High 28005008
2017 Ang1 induces Tie2 dimerization and activation via intermolecular β-sheet formation between membrane-proximal Fibronectin type III domain 3 (Fn3) of Tie2; Tie1 Fn3 is structurally similar and compatible with Tie2/Tie1 heterodimerization by the same mechanism; mutagenesis of key Fn3 residues decreases Ang1-induced Tie2 phosphorylation; Fn2–Fn2 interactions maintain preformed Tie2 oligomerization (mutation increases basal phosphorylation); one PCG-associated Tie2 mutation maps to the Fn2–Fn2 interface and disrupts Tie2 clustering/junctional localization. X-ray crystallography of Tie2 and Tie1 Fn3 domains; mutagenesis of dimerization interfaces; Tie2 phosphorylation assays; structural analysis of disease mutations Proceedings of the National Academy of Sciences of the United States of America High 28396439
2017 Tie2 ECR forms strong dimers in the absence of ligand through membrane-proximal FNIII domains (FNIIIc primarily); two dimer modes are structurally defined; mutagenesis implicates dimer-1 in solution-phase sTie2 dimerization; modeling suggests Ang1 may cross-link Tie2 dimers into higher-order oligomers to explain context-dependent clustering. 2.5-Å resolution X-ray crystal structure of Tie2(FNIIIa-c); small-angle X-ray scattering (SAXS) of sTie2 in solution; mutagenesis of dimer interfaces Proceedings of the National Academy of Sciences of the United States of America High 28396397
2017 Pericyte-expressed Tie2 is functional: silencing Tie2 in pericytes produces a pro-migratory phenotype and controls sprouting angiogenesis; Tie2 downstream signaling in pericytes involves Calpain, Akt, and FOXO3A; pericyte-specific Tie2 deletion (Ng2-Cre) transiently delays retinal angiogenesis but leads to a pro-angiogenic phenotype promoting tumor growth. Pericyte Tie2 siRNA knockdown; in vitro sprouting assay; in vivo spheroid assay; Ng2-Cre-driven conditional Tie2 deletion in mice; retinal angiogenesis and tumor growth assays; signaling pathway analysis (Calpain, Akt, FOXO3A) Nature communications High 28719590
2018 In sepsis, Tie2 protein is suppressed at two levels: (1) MMP14 (MT1-MMP) cleaves the Tie2 N-terminal ectodomain, generating a soluble fragment (mechanistically demonstrated by MMP14 necessity and sufficiency); (2) at the transcriptional level, laminar flow induces Tie2 mRNA via GATA3, and loss of flow/GATA3 in sepsis reduces Tie2 mRNA; both mechanisms operate in vitro, in mice, and in septic human tissues. Western blot and qPCR in TNF-α-treated HUVECs; cecal ligation and puncture mouse model; MMP14 knockdown/overexpression; shear flow experiments; GATA3 knockdown; postmortem kidney biopsies from septic patients Critical care medicine High 29979219
2019 Endocardial-specific loss of Tie2 causes mid-gestation lethality with hyperplastic but simplified trabeculae due to reduced endocardial cell proliferation/sprouting; hyperplastic trabeculae result from enhanced cardiomyocyte proliferation associated with upregulation of Bmp10, increased retinoic acid (RA) signaling, and Erk1/2 hyperphosphorylation; inhibition of RA signaling in utero partially rescues the myocardial phenotype. Endocardial-specific Tie2 conditional knockout mice; histology and proliferation assays; Bmp10 and RA signaling pathway analysis; pharmacological RA receptor antagonist (BMS493) in utero treatment JCI insight High 31112136
2020 EphA4 is a negative regulator of Tie2 signaling in vascular endothelial cells: endothelial EphA4 deletion (EphA4fl/fl/Tie2-Cre mice) enhances pial collateral remodeling, cerebral blood flow, and functional recovery after stroke; EphA4-Tie2 crosstalk is mediated through p-Akt regulation. Endothelial-specific EphA4 knockout using Tie2-Cre; vessel painting for collateral assessment; CBF measurement; peptide inhibition of EphA4; p-Akt signaling assays The Journal of clinical investigation High 31689239
2020 SVEP1 stimulates TEK expression in HUVECs (measured by qPCR); the PCG-associated SVEP1:p.R997C variant abrogates this stimulation, establishing SVEP1 as a transcriptional modifier of TEK expression that contributes to TEK-related PCG penetrance. SVEP1 stimulation of HUVECs; TaqMan qPCR for TEK; transfection of mutant SVEP1 in HEK293 cells; immunofluorescence for SVEP1 in developing SC Investigative ophthalmology & visual science Medium 33027505
2021 SIRT7 negatively regulates TEK/TIE2 expression by binding the transcription factor EST-1 and inducing H3K18 deacetylation at the TEK promoter; Co-IP confirmed direct SIRT7-EST-1 interaction; knockdown of EST-1 removes SIRT7-mediated TEK transcriptional repression. CHIP-qPCR; electrophoretic mobility shift assay (EMSA); promoter reporter assay; Co-IP; siRNA knockdown; RNA-seq Cellular oncology Medium 34797559
2023 VE-PTP (PTPRB) is upregulated in kidney endothelial cells after ischemia-reperfusion injury, inactivating Tie2; genetic deletion of VE-PTP or injection of angiopoietin mimetic Hepta-ANG1 activates Tie2, protects kidneys from IR-AKI, promotes ENTPD1/CD39 expression, and suppresses FOXO1 target genes in the vasculature; a new glomerular endothelial subpopulation emerges with Tie2 activation. VE-PTP conditional knockout mice; Hepta-ANG1 injection; bilateral IR-AKI mouse model; single-cell RNAseq; histology; immunostaining; FOXO1 transcriptome comparison Journal of the American Society of Nephrology : JASN High 36787763
2023 Endothelial Tie2 (but not Tie1) is atheroprotective: deletion of Tie2 in arterial endothelium increases FOXO1 nuclear localization, endothelial adhesion molecule expression, and immune cell accumulation, promoting atherosclerosis; Tie2 is also expressed in aortic fibroblasts, and its silencing increases inflammation-related gene expression in these cells. Arterial endothelium-specific Tie2 deletion in atherosclerotic mouse model; FOXO1 nuclear localization assay; adhesion molecule expression; immune cell quantification; Tie2 silencing in isolated fibroblasts Nature cardiovascular research High 37476204
2017 TEK/Tie2 (and angiopoietin-1/-2) signaling is required for formation of ascending vasa recta (AVR) in the renal medulla; late gestational deletion of Tie2 or both Ang1 and Ang2 prevents AVR formation, leading to medullary interstitial fluid accumulation, cyst formation, loss of medullary vascular bundles, and impaired urine concentrating ability. Conditional Tie2 deletion and Ang1/Ang2 double-knockout mice; histology; urine concentration measurements; transgenic reporter mice for AVR phenotype characterization Journal of the American Society of Nephrology : JASN High 29237738

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. The Journal of clinical investigation 389 22585576
2010 Targeting the ANGPT-TIE2 pathway in malignancy. Nature reviews. Cancer 379 20651738
2008 Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nature genetics 364 19079259
1997 Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circulation research 364 9314838
2005 The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. Journal of cell science 317 15687104
2008 Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nature cell biology 310 18425120
2017 Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nature communications 273 28719590
2007 Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. Journal of immunology (Baltimore, Md. : 1950) 248 17513791
2007 Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends in immunology 235 17981504
2016 Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation. The Journal of clinical investigation 205 27548529
1999 Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration. The Journal of biological chemistry 184 10521483
2016 Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. The Journal of clinical investigation 183 27270174
2014 Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. The Journal of clinical investigation 182 25180601
2003 Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma. Hepatology (Baltimore, Md.) 155 12717391
2010 Angiopoietin-1/Tie2 receptor signaling in vascular quiescence and angiogenesis. Histology and histopathology 152 20054809
2004 Functional significance of Tie2 signaling in the adult vasculature. Recent progress in hormone research 141 14749497
2008 The angiopoietin/Tie-2 system regulates pericyte survival and recruitment in diabetic retinopathy. Investigative ophthalmology & visual science 134 18436850
1998 Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis. British journal of cancer 134 9459145
2013 Variable Somatic TIE2 Mutations in Half of Sporadic Venous Malformations. Molecular syndromology 129 23801934
2005 Oligomerization and multimerization are critical for angiopoietin-1 to bind and phosphorylate Tie2. The Journal of biological chemistry 128 15769741
2002 The angiopoietins and Tie2/Tek: adding to the complexity of cardiovascular development. Seminars in cell & developmental biology 124 11969368
1998 The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene 124 9764820
2006 Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization. Journal of cell science 117 16895971
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
2001 Altered expression of angiopoietins and Tie2 endothelium receptor in psoriasis. The Journal of investigative dermatology 101 11348459
2006 Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nature structural & molecular biology 97 16732286
2015 Common and specific effects of TIE2 mutations causing venous malformations. Human molecular genetics 93 26319232
2016 Gene control of tyrosine kinase TIE2 and vascular manifestations of infections. Proceedings of the National Academy of Sciences of the United States of America 88 26884170
2017 Angiopoietins and Tie2 in vascular inflammation. Current opinion in hematology 86 28582314
2013 Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence 86 23652985
2019 Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease. Expert opinion on investigational drugs 83 31513439
2013 The angiopoietin:Tie 2 interaction: a potential target for future therapies in human vascular disease. Cytokine & growth factor reviews 82 23838360
2002 Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma. Hepatology (Baltimore, Md.) 81 11915032
1997 Expression and function of murine receptor tyrosine kinases, TIE and TEK, in hematopoietic stem cells. Blood 81 9192754
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
1998 Characterization of TEK receptor tyrosine kinase and its ligands, Angiopoietins, in human hematopoietic progenitor cells. International immunology 77 9723709
2021 Targeting Tie2 in the Tumor Microenvironment: From Angiogenesis to Dissemination. Cancers 76 34830883
1995 GRB2 and SH-PTP2: potentially important endothelial signaling molecules downstream of the TEK/TIE2 receptor tyrosine kinase. Oncogene 74 7478529
2003 A unique autophosphorylation site on Tie2/Tek mediates Dok-R phosphotyrosine binding domain binding and function. Molecular and cellular biology 68 12665569
2013 Mending leaky blood vessels: the angiopoietin-Tie2 pathway in sepsis. The Journal of pharmacology and experimental therapeutics 65 23378191
2017 The Angiopoietin-Tie2 Signaling Axis in Systemic Inflammation. Journal of the American Society of Nephrology : JASN 63 28465380
2017 Ascending Vasa Recta Are Angiopoietin/Tie2-Dependent Lymphatic-Like Vessels. Journal of the American Society of Nephrology : JASN 63 29237738
2016 Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema. Current diabetes reports 62 27778249
2016 Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII. eLife 62 28005008
2008 Intra and extravascular transmembrane signalling of angiopoietin-1-Tie2 receptor in health and disease. Journal of cellular and molecular medicine 62 18266978
2008 Tie2: a journey from normal angiogenesis to cancer and beyond. Histology and histopathology 60 18366015
2003 Angiopoietin/Tek interactions regulate mmp-9 expression and retinal neovascularization. Laboratory investigation; a journal of technical methods and pathology 59 14615417
2009 Tie2 is tied at the cell-cell contacts and to extracellular matrix by angiopoietin-1. Experimental & molecular medicine 57 19293632
2005 Expressions and clinical significances of angiopoietin-1, -2 and Tie2 in human gastric cancer. Biochemical and biophysical research communications 56 16185665
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
2021 Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19. JCI insight 55 34506304
2010 Tie2/TEK modulates the interaction of glioma and brain tumor stem cells with endothelial cells and promotes an invasive phenotype. Oncotarget 54 21321379
2020 The Angiopoietin-Tie2 Pathway in Critical Illness. Critical care clinics 53 32172809
2013 Circulating angiopoietin-2, its soluble receptor Tie-2, and mortality in the general population. European journal of heart failure 50 23901057
2010 Zebrafish Tie-2 shares a redundant role with Tie-1 in heart development and regulates vessel integrity. Disease models & mechanisms 50 21045210
2000 Tek/Tie2 signaling: new and old partners. Cancer metastasis reviews 46 11191051
2002 Expression of angiopoietin-1 and its receptor TEK in hematopoietic cells from patients with myeloid leukemia. Leukemia research 45 11755466
2017 TIE-2 expressing monocytes in human cancers. Oncoimmunology 44 28507810
2004 Targeting the Tie2/Tek receptor in astrocytomas. The American journal of pathology 44 14742253
2006 Angiopoietin-1, angiopoietin-2 and Tie-2 expression in eutopic endometrium in advanced endometriosis. Molecular human reproduction 43 16723371
2015 TIE-2-expressing monocytes are lymphangiogenic and associate specifically with lymphatics of human breast cancer. Oncoimmunology 42 27057438
2002 Tie-2 and angiopoietin-1 expression in human thyroid tumors. Thyroid : official journal of the American Thyroid Association 42 11916292
2023 Activation of Angiopoietin-Tie2 Signaling Protects the Kidney from Ischemic Injury by Modulation of Endothelial-Specific Pathways. Journal of the American Society of Nephrology : JASN 39 36787763
2006 Potential role of soluble angiopoietin-2 and Tie-2 in patients with inflammatory bowel disease. European journal of clinical investigation 39 16436095
2020 EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke. The Journal of clinical investigation 38 31689239
2016 Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling. The Journal of clinical investigation 38 27548526
2006 Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies. European journal of haematology 38 16978237
2004 Expression and function of the angiopoietin receptor Tie-2 in human eosinophils. The Journal of allergy and clinical immunology 38 15536413
2017 Role of Angiopoietins and Tie-2 in Diabetic Retinopathy. Electronic physician 37 28979738
2020 SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma. Investigative ophthalmology & visual science 36 33027505
2006 Nitric oxide regulates Angiopoietin1/Tie2 expression after stroke. Neuroscience letters 36 16762501
1997 Tie2 receptor expression and phosphorylation in cultured cells and mouse tissues. European journal of biochemistry 36 9108247
2017 Angiopoietin receptor TEK interacts with CYP1B1 in primary congenital glaucoma. Human genetics 35 28620713
2017 Review of the endothelial pathogenic mechanism of TIE2-related venous malformation. Journal of vascular surgery. Venous and lymphatic disorders 35 28818232
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
2005 Angiopoietin/Tie2 signaling, tumor angiogenesis and inflammatory diseases. Frontiers in bioscience : a journal and virtual library 35 15569607
2019 Endothelial YAP1 in Regenerative Lung Growth through the Angiopoietin-Tie2 Pathway. American journal of respiratory cell and molecular biology 34 30156429
2010 Increased expression of angiopoietins and Tie2 in the lungs of chronic asthmatic mice. American journal of respiratory cell and molecular biology 30 20463289
2008 Vaccination against TIE2 reduces atherosclerosis. Atherosclerosis 30 19022447
2016 Tie-2 regulates the stemness and metastatic properties of prostate cancer cells. Oncotarget 29 25978029
2011 Myoferlin gene silencing decreases Tie-2 expression in vitro and angiogenesis in vivo. Vascular pharmacology 29 21586340
2011 Somatic mutations in exon 17 of the TEK gene in vascular tumors and vascular malformations. Journal of vascular surgery 29 21962923
2020 Notoginsenoside R1 activates the Ang2/Tie2 pathway to promote angiogenesis. Phytomedicine : international journal of phytotherapy and phytopharmacology 28 32823242
2014 Signaling Network Map of Endothelial TEK Tyrosine Kinase. Journal of signal transduction 28 25371820
2005 Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents. The Journal of thoracic and cardiovascular surgery 28 15678035
2020 The Angiopoietin/Tie2 Pathway in Hepatocellular Carcinoma. Cells 24 33143149
2018 Molecular Regulation of Acute Tie2 Suppression in Sepsis. Critical care medicine 24 29979219
2017 Dimerization of Tie2 mediated by its membrane-proximal FNIII domains. Proceedings of the National Academy of Sciences of the United States of America 23 28396397
2016 Novel TIE-2 inhibitor BAY-826 displays in vivo efficacy in experimental syngeneic murine glioma models. Journal of neurochemistry 23 27787897
2019 Tie2 regulates endocardial sprouting and myocardial trabeculation. JCI insight 22 31112136
2004 Differential expression of the Tie-2 receptor and its ligands in human pancreatic tumors. Journal of the American College of Surgeons 22 15501112
1998 Functional analysis of the endothelial cell-specific Tie2/Tek promoter identifies unique protein-binding elements. The Biochemical journal 22 9461528
2021 Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages. Cell death & disease 21 34294700
2016 Hydroxysafflor Yellow A Promotes Angiogenesis via the Angiopoietin 1/ Tie-2 Signaling Pathway. Journal of vascular research 21 27894114
2014 Tie2 and Eph receptor tyrosine kinase activation and signaling. Cold Spring Harbor perspectives in biology 21 24478383
2012 Circulating angiopoietin and Tie-2 levels in systemic sclerosis. Rheumatology international 21 22461185
2023 The angiopoietin receptor Tie2 is atheroprotective in arterial endothelium. Nature cardiovascular research 20 37476204
2021 SIRT7 interacts with TEK (TIE2) to promote adriamycin induced metastasis in breast cancer. Cellular oncology (Dordrecht, Netherlands) 20 34797559

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