Disease relevance of TEK

• Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth [1].
• To assess the potential role of Tie2 and its ligands angiopoietin-1 and angiopoietin-2 in tumor vascularization, we analyzed their expression pattern in human gliomas [2].
• Recent studies have shown that the angiopoietin-Tie2 system is a major regulator of vascular integrity and is involved in pathologic angiogenesis [3].
• Potential role of the angiopoietin/tie2 system in ischemia-induced retinal neovascularization [3].
• Expression of the angopoietin-1, angopoietin-2, Tie2, and vascular endothelial growth factor gene in epithelial ovarian cancer [4].

High impact information on TEK

• (this issue of Cell) demonstrate that HSCs that express the receptor tyrosine kinase Tie2 are quiescent [5].
• Ang-1, the ligand for Tie2, enhanced the ability of HSCs to become quiescent and also induced their adhesion to bone, protecting them from stresses that suppress hematopoiesis [5].
• Only one other family of receptor tyrosine kinases, comprising TIE1 and TIE2, is largely endothelial cell specific [6].
• Although Angiopoietin-1 binds and induces the tyrosine phosphorylation of TIE2, it does not directly promote the growth of cultured endothelial cells [7].
• A missense mutation resulting in an arginine-to-tryptophan substitution at position 849 in the kinase domain of the receptor tyrosine kinase TIE2 segregates with dominantly inherited VM in two unrelated families [8].

Chemical compound and disease context of TEK

• CONCLUSIONS: These findings suggest that the Ang/Tie2 pathway plays a significant role in human breast tumor angiogenesis but provide no initial evidence for direct regulation of the pathway by estrogen [9].
• Expression of angiopoietin-1, angiopoietin-2, and Tie2 genes in normal ovary with corpus luteum and in ovarian cancer [10].
• METHODS: Ang/Tie2 gene expression was assessed in rats that had been exposed to hypoxia (ie, 10% O2) for 1, 3, or 7 days [11].
• The extracellular domain of the receptor tyrosine kinase Tie2/TEK (exTEK) has been used as an angiopoietin decoy to study the role of angiopoietins in the tumor-host interactions, using a syngeneic model of experimental metastases and subcutaneous tumor [12].
• Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway [13].

Biological context of TEK

• Angiopoietin 1 (Ang1), a ligand for the receptor tyrosine kinase Tie2, regulates the formation and stabilization of the blood vessel network during embryogenesis [14].
• Recombinant Ang2(443) binds to the Tie2 receptor but does not induce Tie2 phosphorylation [15].
• Then we analyzed the molecular structure of the variants with SDS-PAGE and rotary metal-shadowing transmission electron microscopy (RMSTEM) and determined the effects of these variants on the binding and activation of Tie2 [16].
• Recently discovered, Ang1 and Ang2, upon binding to Tie2 receptor, modulate vascular permeability and integrity, contributing to angiogenesis [17].
• Furthermore, Tyr-1101 of Tie2 was identified as the primary binding site for the SH2 domain of ShcA [18].

Anatomical context of TEK

• We found Tie2 mRNA and protein up-regulated with a concomitant increase in cellular responsiveness to Ang1 in most hemangioma-derived endothelial cells [19].
• Fibroblasts stably transfected with Tie2 receptor exhibit chemotactic responses for both angiopoietin-1 and angiopoietin-2 [20].
• Flow cytometric analysis of bone marrow cells revealed that TEK was expressed in 27% of CD34+ cells, 20% of c-KIT+ cells and 26% of CD34+CD38- cells, indicating that TEK is expressed in a subset of primitive hematopoietic stem cells (HSC) [21].
• TEK was also expressed in 20% of CD19+ B lymphocytes but not in other lineage-committed cells [21].
• Reverse transcription-PCR and Western blotting analyses confirmed the expression of Ang1 and Tie2 in glomeruli and of Ang1 in cultured podocytes [22].

Associations of TEK with chemical compounds

• Herein, we report that Ang1 and Ang2 (1 nM) are both capable of mediating a rapid Tie2 phosphorylation and a rapid, progressive and sustained endothelial PAF synthesis maximal within 4 h (1695% and 851% increase, respectively) [17].
• The survival effect of high concentration Ang2 was blocked by pre-treatment with soluble Tie2 receptor and the PI 3'-kinase-specific inhibitors, wortmannin and LY294002 [23].
• No significant associations were observed between the other members of the Ang/Tie2 gene family and patient age, tumor size, lymph node status, tumor grade, vascular invasion, tumor vascularity, vascular maturation, thymidine phosphorylase, or vascular endothelial growth factor A expression (P > 0.05 for all) [9].
• Cyclical mechanical stretch increased (and Gö6976 or herbimycin A abrogated these increases) the immunohistochemical labelling of angiopoietin-2 and Tie2 receptor after a 6 h stretch [24].
• Stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1 [25].

Physical interactions of TEK

• Structure of the angiopoietin-2 receptor binding domain and identification of surfaces involved in Tie2 recognition [26].
• Moreover, co-immunoprecipitation experiments revealed the presence of a STAT5/Tie2 molecular complex in neointima vessels from advanced, but not from early, lesions [27].
• ABIN-2 also interacts with the endothelial receptor Tie2 [28].
• NERF2 can bind to the Tie2 promoter Ets sites in electrophoretic mobility shift assays [29].
• 1 Angiopoietin-1 (Ang1) is an angiogenic growth factor that binds to the Tie2 receptor on vascular endothelium, promoting blood vessel maturation and integrity [30].

Regulatory relationships of TEK

• Tie2 was localized in vascularized regions of fibrovascular membranes and was co- expressed with VEGF and factor VIII [31].
• Together, our results identified a novel interaction between Tie2 with the adapter molecule ShcA and suggested that this interaction may play a role in the regulation of migration and three-dimensional organization of endothelial cells induced by angiopoietin-1 [18].
• Our results suggest that the autocrine/paracrine signaling of the Ang/Tie2 system is important for the up-regulated angiogenesis in the RA synovium, as well as for synoviocyte behavior, by regulating chemotactic cell movement [32].
• These findings indicate that the TEK-TEK ligand signaling pathway is regulated in a refined manner and is involved in hematopoietic cell-microenvironment interaction [21].
• These data suggest that it is endothelial induction of Ang-2 in tumours that regulates vessel stability and supports targeting Tie2 as an effective novel anti-angiogenic therapy in clear cell RCCs [33].

Other interactions of TEK

• VEGF receptors and Tie2 expression was investigated using immunohistochemical assays with monoclonal antibodies on frozen sections in a series of 918 and 909 patients respectively [34].
• VEGFR-1 and VEGFR-2 and Tie2 were correlated with long-term (median, 11.3 years) patients' outcome [34].
• In multivariate analysis (Cox model), VEGFR-1 and Tie2 immunoexpressions were identified as independent prognostic indicators [34].
• TEK and ACVRL1 could essentially be excluded [35].
• CONCLUSIONS: In advanced lesions, the activation of the Tie2-mediated STAT5 signaling pathway may negatively regulate vessel growth [27].

Analytical, diagnostic and therapeutic context of TEK

• In a transwell coculture system, we observed that myeloma cells up-regulated the Ang-1 receptor Tie2 in human BM endothelial cells [36].
• High-power, multiple-color, immunofluorescence analyses and additional antibodies (specific for particular components of the glomerular filtration barrier) were used to determine the exact locations of Ang1 and Tie2 in the glomerular capillary wall [22].
• We, therefore, analyzed blood cells of healthy donors and leukemia patients for expression of TEK and ang-1 by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Northern blotting [37].
• Genetic engineering of precise multimers of the receptor-binding domain of angiopoietin-1, using surrogate multimerization motifs, reveals that tetramers are the minimal size required for activating endothelial Tie2 receptors [38].
• Using a novel collagen-induced arthritis synovial window model, we demonstrated that Tie2 signaling regulated arthritis angiogenesis in vivo [39].

References