Disease relevance of Tek

• Angiopoietin/Tek interactions regulate mmp-9 expression and retinal neovascularization [1].
• Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway [2].
• In conclusion, consistent with the immature phenotype of the cystic epithelium, expression of VEGF, VEGFRs, Ang-1 and Tie-2 is strongly upregulated in cholangiocytes from polycystic liver diseases [3].
• Targeting the Tie2/Tek receptor in astrocytomas [4].
• Angiopoietin-1, angiopoietin-2 and Tie-2 in tumour and non-tumour tissues during growth of experimental melanoma [5].

High impact information on Tek

• Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche [6].
• Here, we demonstrate that HSCs expressing the receptor tyrosine kinase Tie2 are quiescent and antiapoptotic, and comprise a side-population (SP) of HSCs, which adhere to osteoblasts (OBs) in the BM niche [6].
• We transduced bone marrow progenitors with lentiviral vectors expressing genes from transcription-regulatory elements of Tie2/Tek gene [7].
• Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation [8].
• This result contrasts with previous reports on Tie-2 function in vasculogenesis and/or endothelial cell survival [8].

Chemical compound and disease context of Tek

• Macrophage-stimulating protein activates STK receptor tyrosine kinase on osteoclasts and facilitates bone resorption by osteoclast-like cells [9].

Biological context of Tek

• These data suggest that VEGF-A-induced up-regulation of Tie2 expression on the regenerating vasculature after BM suppression supports the assembly of sinusoidal endothelial cells, thereby promoting reconstitution of hematopoiesis [10].
• Using transgenic mice where the Tie2 promoter drives the reporter LacZ gene (Tie2-LacZ), we demonstrate that at steady state, there was minimal expression of Tie2 in the BM vasculature [10].
• In this study, by using reverse transcription polymerase chain reaction and Northern and Western blotting, we demonstrated that Ang-1, Ang-2, and Tie-2 were expressed during early metanephrogenesis when interstitial and glomerular capillaries begin to form [11].
• Furthermore, treatment of cells with IL-1beta indirectly (via down-regulation of Ang-1) led to a decrease in Tie-2 autophosphorylation levels in HUVECs [12].
• This mutant Tie-2 receptor is functionally inactive as shown by the lack of ligand binding and receptor phosphorylation [13].

Anatomical context of Tek

• We have cloned a 4.2-kb murine cDNA encoding the Tek receptor tyrosine kinase (RTK), which is expressed in endothelial cells and their progenitors [14].
• On the basis of these observations, we propose that Ang signaling regulates lymphatic vessel formation through Tie2 [15].
• Immunoblotting suggested an increase of total and tyrosine-phosphorylated Tie-2 proteins in null mutant versus wild-type kidneys, and electron microscopy confirmed disorganized capillaries and adjacent cells in cortical peritubular spaces in mutant neonate kidneys [16].
• Ang1 and Tie2 decreased in trophoblastic giant cells and Ang2 was decreased in placental endothelial cells [17].
• Ang2 expression in the highly proliferative tumor vascular endothelium was also increased, as was phosphorylated Tie2/Tek [18].

Associations of Tek with chemical compounds

• Angiopoietin (Ang) signaling plays a role in angiogenesis and remodeling of blood vessels through the receptor tyrosine kinase Tie2, which is expressed on blood vessel endothelial cells (BECs) [15].
• However, after 5-fluorouracil (5-FU) treatment, there was a rapid increase in plasma vascular endothelial growth factor A (VEGF-A) levels and expansion of Tie2-positive neovessels [10].
• Inoculation of mice with cells expressing soluble VEGF receptor-2 or Tie-2 blocked the increase in vascular density normally observed after administration of testosterone to castrated mice [19].
• COMP-Ang1-mediated inhibition of increased NF-kappaB-DNA binding in nuclear extracts from HUVECs grown in high glucose was significantly blocked by soluble Tie2 receptor-Fc [20].
• In an attempt to identify downstream signaling partners of the Tek receptor, we have used the yeast two-hybrid system to identify phosphotyrosine-dependent interactions [21].

Physical interactions of Tek

• The effects of inhibiting angiopoietin binding to the Tie-2 receptor was studied in newborn mice with experimentally induced retinal neovascularization [1].
• Mapping of the phosphotyrosine-interaction domain within Dok-R shows that Dok-R interacts with Tek through a PTB domain [21].

Co-localisations of Tek

• Immunohistochemistry disclosed that Tie2 colocalized with platelet-endothelial-cell-adhesion-molecule in endothelial cells from normal mouse adrenal [22].

Regulatory relationships of Tek

• Dok-R is coexpressed with Tek in a number of endothelial cell lines [21].
• Phosphoinositide 3-kinase (PI3K) is activated by transmembrane tyrosine kinases such as vascular endothelial growth factor (VEGF) receptors and Tie2 (tunica intima endothelial kinase 2), both of which are key regulators of vascular development [23].
• Enforced expression of SDF-1 under the control of vascular-specific Tie-2 regulatory sequences could completely rescue the reduction of HSCs but not myeloid cells in SDF-1(-/-) bone marrow [24].

Other interactions of Tek

• In this study, we reveal that lymphatic vascular endothelial hyaluronan receptor 1-positive (LYVE-1(+)) lymphatic endothelial cells (LECs) express Tie2 in both embryonic and adult settings, indicating that Ang signaling occurs in lymphatic vessels [15].
• Consistent with this notion, we showed with the primitive hematopoietic colony assay that primitive erythropoietic progenitors are enriched in PECAM-1- and Tie2-positive cells [25].
• Exogenous VEGF-A and Ang-1 stimulated Tie2 expression in the BM vasculature [10].
• Furthermore, Tie-1 was strongly induced during repair with a prolonged expression in diabetic mice, whereas Tie-2 expression was constitutive during normal repair but completely absent in diabetes-impaired healing [26].
• The RT-PCR analysis of the retinas of the Tek-treated animals showed a similar (80%; p = 0.001) inhibition of the MMP-9 expression, which correlated with the decrease in angiogenesis [1].

Analytical, diagnostic and therapeutic context of Tek

• Nude mouse xenografts revealed that interference with either the VEGF receptor pathway or the Tie-2 pathway resulted in a significant inhibition of tumor growth and tumor angiogenesis [2].
• Using Western blotting of protein extracted from whole organs, Tie-2 protein was detected between E14 and P8 with tyrosine phosphorylated Tie-2 evident from E18 [27].
• Using in situ hybridization and immunohistochemistry, Tie-2 was detected in capillaries of the nephrogenic cortex, glomerular tufts, cortical interstitium, and medulla including vessels in the vasa recta [27].
• Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR we measured Ang-1, Ang-2 and Tie-2 mRNA levels in the tumour, bone marrow, liver and spleen [5].
• In situ hybridization studies showed that Ang-1 and Tie-2 were detected in the cyto/syncytiotrophoblast bilayer in first-trimester placenta, whereas Ang-2 mRNA was restricted to the cytotrophoblast, suggesting their role in trophoblast function [28].

References