Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TIE2 is a receptor-like tyrosine kinase expressed almost exclusively in endothelial cells and early hemopoietic cells and required for the normal development of vascular structures during embryogenesis. We report the identification of a secreted ligand for TIE2, termed Angiopoietin-1, using a novel expression cloning technique that involves intracellular trapping and detection of the ligand in COS cells. The structure of Angiopoietin-1 differs from that of known angiogenic factors or other ligands for receptor tyrosine kinases. Although Angiopoietin-1 binds and induces the tyrosine phosphorylation of TIE2, it does not directly promote the growth of cultured endothelial cells. However, its expression in close proximity with developing blood vessels implicates Angiopoietin-1 in endothelial developmental processes.
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PMID:Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. 898 Feb 21

Vascular endothelial growth factor (VEGF), which acts via members of a family of endothelial-specific receptor tyrosine kinases, is the only factor that has been shown definitively to play a role in the formation of the embryonic vasculature. Only one other family of receptor tyrosine kinases, comprising TIE1 and TIE2, is largely endothelial cell specific. We have recently cloned a ligand for TIE2, termed Angiopoietin-1. Here we show that mice engineered to lack Angiopoietin-1 display angiogenic deficits reminiscent of those previously seen in mice lacking TIE2, demonstrating that Angiopoietin-1 is a primary physiologic ligand for TIE2 and that it has critical in vivo angiogenic actions that are distinct from VEGF and that are not reflected in the classic in vitro assays used to characterize VEGF. Angiopoietin-1 seems to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.
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PMID:Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. 898 Feb 21

Vascular endothelial growth factor (VEGF) is a prime regulator of normal and pathological angiogenesis. Three related endothelial cell growth factors, VEGF-B, VEGF-C, and VEGF-D were recently cloned. We have here studied the regulation of VEGF-C, a lymphatic endothelial growth factor, by angiogenic proinflammatory cytokines. Interleukin (IL)-1beta induced a concentration- and a time-dependent increase in VEGF-C, but not in VEGF-B, mRNA steady-state levels in human lung fibroblasts. The increase in VEGF-C mRNA levels was mainly due to increased transcription rather than elevated mRNA stability as detected by the nuclear run-on method and by following mRNA decay in the presence of an inhibitor of transcription, respectively. In contrast, angiopoietin-1 mRNA, encoding the ligand for the endothelial-specific Tek/Tie-2 receptor, was down-regulated by IL-1beta. Tumor necrosis factor-alpha and IL-1alpha also elevated VEGF-C mRNA steady-state levels, whereas the IL-1 receptor antagonist and dexamethasone inhibited the effect of IL-1beta. Experiments with cycloheximide indicated that the effect of IL-1beta was independent of protein synthesis. Hypoxia, which is an important inducer of VEGF expression, had no effect on VEGF-B or VEGF-C mRNA levels. IL-1beta and tumor necrosis factor-alpha also stimulated the production of VEGF-C protein by the fibroblasts. Cytokines and growth factors have previously been shown to down-regulate VEGF receptors in vascular endothelial cells. We found that the mRNA for the VEGF- and VEGF-C-binding VEGFR-2 (KDR/Flk-1) was stimulated by IL-1beta in human umbilical vein endothelial cells, whereas the mRNA levels of VEGFR-1 (Flt-1) and VEGFR-3 (Flt-4) were not altered. Our data suggest that in addition to VEGF, VEGF-C may also serve as an endothelial stimulus at sites of cytokine activation. In particular, these results raise the possibility that certain proinflammatory cytokines regulate the lymphatic vessels indirectly via VEGF-C.
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PMID:Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. 952 52

As shown previously, TIE1 and TIE2 receptor tyrosine kinases are specifically expressed in endothelial cells during embryonic angiogenesis. A detailed analysis of the vascular malformations of homozygous mice for a targeting mutation of both receptors was performed at the histological and cellular level. The data demonstrate that the TIE1 and TIE2 receptor inversely and concomitantly mediate interactions between endothelial cells with their extracellular matrix and with surrounding mesenchymal cells. These interactions are obviously crucial for normal endothelial cell motility and/or attachment and also for recruitment of periendothelial cells. The analysis of the TIE2-deficient embryos demonstrates how these cell/cell- and cell/matrix interactions subsequently influence the formation of normally structured tissue folds that divide the vessel lumen. They are also essential for the formation of vessel loops that compose a new vascular network and for the development of the ventricle in the heart. Fold and loop formation follow the principles of intussusceptive microvascular growth. The localization of the cardiovascular malformations corresponds to the temporal and spatial expression pattern of the TIE2 receptor. Angiopoietin-1, a ligand that activates the TIE2 receptor, is expressed in mesenchymal cells surrounding the endothelium. This local relationship is indicative of a paracrine regulation.
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PMID:TIE1 and TIE2 receptor tyrosine kinases inversely regulate embryonic angiogenesis by the mechanism of intussusceptive microvascular growth. 968 59

TEK, or TIE-2, is a receptor tyrosine kinase (RTK) that is known as a functioning molecule of vascular endothelial cells. TEK comprises a subfamily of RTK with TIE, and these two receptors play critical roles in vascular maturation, maintenance of integrity and remodeling. We generated mAb against the extracellular domain of human TEK protein to elucidate its expression pattern in human hematopoietic cells. 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). TEK was also expressed in 20% of CD19+ B lymphocytes but not in other lineage-committed cells. Progenitor assays in methylcellulose culture showed that CD34+TEK+ cells formed significantly less BFU-E and CFU-Mix than CD34+TEK- cells, but there was no difference in the number of CFU-GM between these two populations. Two recently identified TEK ligands, termed Angiopoietin-1 and -2, bound to TEK with similar affinities, and Angiopoietin-1 effectively induced TEK phosphorylation in hematopoietic cells. Angiopoietin-2 also induced a low level of TEK phosphorylation and weakened the phosphorylation induced by Angiopoietin-1, suggestive of an elaborate regulator of the TEK-TEK ligand signaling pathway. Although neither ligands affected the proliferation of TEK-transfected hematopoietic cells or the colony formation of CD34+TEK+ bone marrow cells, both promoted the adhesion of TEK-transfected hematopoietic cells to a collagen matrix or a layer of bone marrow stromal cells. These findings indicate that the TEK-TEK ligand signaling pathway is regulated in a refined manner and is involved in hematopoietic cell-microenvironment interaction.
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PMID:Characterization of TEK receptor tyrosine kinase and its ligands, Angiopoietins, in human hematopoietic progenitor cells. 972 9

We have investigated the function of TIE2/TEK receptor tyrosine kinase in the development of definitive hematopoiesis. In the vitelline artery at 9.5 days postcoitum (d.p.c.), TIE2+ hematopoietic cells aggregated and adhered to TIE2+ endothelial cells. Soluble TIE2-Fc chimeric protein inhibited the development of hematopoiesis and angiogenesis in the para-aortic splanchnopleural mesoderm (P-Sp) explant culture, and TIE2-deficient mice showed severely impaired definitive hematopoiesis. An in vitro study revealed that Angiopoietin-1 but not Angiopoietin-2 promoted the adhesion to fibronectin (FN) through integrins in TIE2-transfected cells and primary TIE2+ cells sorted from 9.5 d.p.c. P-Sp. Adhesion of TIE2+ cells induced by Angiopoietin-1 enhanced the proliferation of hematopoietic progenitor cells.
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PMID:Critical role of the TIE2 endothelial cell receptor in the development of definitive hematopoiesis. 984 89

Recent studies have shown that long-term repopulating hematopoietic stem cells (HSCs) first appear in the aorta-gonad-mesonephros (AGM) region. Our immunohistochemistry study showed that TEK+ cells existed in the AGM region. Approximately 5% of AGM cells were TEK+, and most of these were CD34(+) and c-Kit+. We then established a coculture system of AGM cells using a stromal cell line, OP9, which is deficient in macrophage colony-stimulating factor (M-CSF). With this system, we showed that AGM cells at 10.5 days postcoitum (dpc) differentiated and proliferated into both hematopoietic and endothelial cells. Proliferating hematopoietic cells contained a significant number of colony-forming cells in culture (CFU-C) and in spleen (CFU-S). Among primary AGM cells at 10.5 dpc, sorted TEK+ AGM cells generated hematopoietic cells and platelet endothelial cell adhesion molecule (PECAM)-1(+) endothelial cells on the OP9 stromal layer, while TEK- cells did not. When a ligand for TEK, angiopoietin-1, was added to the single-cell culture of AGM, endothelial cell growth was detected in the wells where hematopoietic colonies grew. Although the incidence was still low (1/135), we showed that single TEK+ cells generated hematopoietic cells and endothelial cells simultaneously, using a single-cell deposition system. This in vitro coculture system shows that the TEK+ fraction of primary AGM cells is a candidate for hemangioblasts, which can differentiate into both hematopoietic cells and endothelial cells.
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PMID:In vitro hematopoietic and endothelial cell development from cells expressing TEK receptor in murine aorta-gonad-mesonephros region. 1002 83

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcriptional regulator that heterodimerizes with Per-ARNT-Sim (PAS) proteins. ARNT also dimerizes with hypoxia inducible factor1alpha (HIF1alpha), inducing expression of vascular endothelial cell growth factor (VEGF) to promote angiogenesis. The angiogenesis/vasculogenesis pathway is required for embryonic survival and includes several receptors (VEGFR1, VEGFR2, Tie2) and ligands (VEGF, Ang1, Ang2, neuropillin). Transgenic knockout of ARNT in mice is lethal due to abnormal placentation. This study examines the VEGF pathway in GD9.5 embryos of wild-type (+/+), heterozygous (+/-), or knockout (-/-) ARNT genotype. All genotypes expressed abundant VEGF in trophoblastic giant cells. However, -/- conceptuses had less VEGFR2 in placental labyrinth and trophoblastic giant cells. Ang1 and Tie2 decreased in trophoblastic giant cells and Ang2 was decreased in placental endothelial cells. Abnormal development of the labyrinth correlated with decreased binding of VEGF and decreased expression of VEGFR2. In addition, VEGFR2 seemed to be the primary VEGF binding receptor in the labyrinth and blood lacunae of the placenta, as binding could be eliminated by masking the VEGFR2 receptor with inactive antibody complex. VEGFR1 may be primarily responsible for binding of VEGF to yolk sac and embryonic tissues, as masking VEGFR2 did not reduce VEGF binding in those areas, and it is interesting that major structural defects were also not found in those regions. In summary, in the ARNT knockout conceptus, the impact of ARNT deficiency on placental expression of VEGFR2 seems to provide an explanation for the failure of the placental labyrinth to progress, whereas the vascularization of the yolk sac and embryo appear relatively unaffected on GD9.5. Published 2000 Wiley-Liss, Inc.
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PMID:Placental defects in ARNT-knockout conceptus correlate with localized decreases in VEGF-R2, Ang-1, and Tie-2. 1108 52

Vascular polarity is a fundamental feature of angiogenesis and left-right asymmetry of the vascular network. Contrary to this importance, the molecular basis of vascular polarity is completely unknown. In this report, we show that the combinatorial function of angiopoietin-1 and the orphan receptor TIE1 is critical specifically for the development of the right-hand side venous system but is dispensable for the left-hand side venous system. Furthermore, our current finding reveals the existence of a distinct genetic program for the establishment of the right-hand side and left-hand side vascular networks well before the network asymmetry becomes morphologically discernible.
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PMID:A combinatorial role of angiopoietin-1 and orphan receptor TIE1 pathways in establishing vascular polarity during angiogenesis. 1117 28

Vascular endothelial growth factor (VEGF) is a major inducer of tumor angiogenesis and edema in human astrocytomas by its interaction with cognate endothelial-specific receptors (VEGFR1/R2). Tie1 and Tie2/Tek are more recently identified endothelial-specific receptors, with angiopoietins being ligands for the latter. These angiogenic factors and receptors are crucial for the maturation of the vascular system, but their role in tumor angiogenesis, particularly in astrocytomas, is unknown. In this study, we demonstrate that the angiopoietin family member Ang1 is expressed by some of the astrocytoma cell lines. In contrast to VEGF, Ang1 is down regulated by hypoxia. Ang2 was not overexpressed. Expression profiles of low-grade astrocytoma specimens were similar to those of normal brain, with low levels of Ang1, Ang2, and VEGF expression. Glioblastoma multiforme expressed higher levels of Angl, but not to the same degree as pseudopalisading astrocytoma cells around necrotic and hypoxic zones expressed VEGF, as shown in previous studies. Ang2 expression in the highly proliferative tumor vascular endothelium was also increased, as was phosphorylated Tie2/Tek. The expression profile of these angiogenic factors and their endothelial cell receptors in human glioblastomas multiforme was similar to that in a transgenic mouse model of glioblastoma multiforme. These data suggest that both VEGF and angiopoietins are involved in regulating tumor angiogenesis in human astrocytomas.
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PMID:Expression and hypoxic regulation of angiopoietins in human astrocytomas. 1130 11


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