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)

In mammals, the continuous production of hematopoietic cells (HCs) is sustained by a small number of hematopoietic stem cells (HSCs) residing in the bone marrow. Early HSC activity arises in the aorta-gonad mesonephros region, within cells localized to the ventral floor of the major blood vessels, suggesting that the first HSCs may be derived from cells capable of giving rise to the hematopoietic system and to the endothelial cells of the vasculature. TIE1 (TIE) and TIE2 (TEK) are related receptor tyrosine kinases with an embryonic expression pattern in endothelial cells, their precursors, and HCs, suggestive of a role in the divergence and function of both lineages. Indeed, gene targeting approaches have shown that TIE1, TIE2, and ligands for TIE2, the angiopoietins, are essential for vascular development and maintenance. To explore possible roles for these receptors in HCs, we have examined the ability of embryonic cells lacking both TIE1 and TIE2 to contribute to developmental and adult hematopoiesis by generating chimeric animals between normal embryonic cells and cells lacking these receptors. We show here that TIE receptors are not required for differentiation and proliferation of definitive hematopoietic lineages in the embryo and fetus; surprisingly, however, these receptors are specifically required during postnatal bone marrow hematopoiesis.
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PMID:Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis. 1453 Mar 87

Vein graft failure within the first month after bypass surgery is largely because of thrombosis. However, systemic study of thrombus formation in vein grafts is still lacking, and few effective techniques are available to prevent this event. Herein, we analyzed the kinetics of thrombosis and tested the effectiveness of locally applied aspirin on prevention of the disease in a mouse model. En face analysis of vein grafts revealed that 67+/-12% and 54+/-17% of the surface areas were covered by microthrombi at 1 and 3 days, respectively. Thrombus generation was also identified by labeling of platelets and fibrin, which occurred in 35 grafts examined at 1 and 3 days and 1, 2, 4, and 8 weeks. In a fifth of grafts, the thrombus occluded the vessel lumen by > or =1/4. Furthermore, a significant loss of endothelial cells was evidenced by beta-gal staining for vein grafts in transgenic mice expressing LacZ gene controlled by TIE2-endothelial specific gene promoter. Following thrombosis, neointimal lesions were significantly increased by 4-fold 2 weeks after the operation. When vein grafts were treated locally with aspirin in pluronic gel-127, the thrombus area was significantly reduced (P<0.005) at 1, 4, and 8 weeks. Interestingly, neointimal lesions were markedly reduced in the local, but not oral, aspirin-treated group at 4 and 8 weeks by 50% to 70% (P<0.005). The mechanism of reduced lesions by locally applied aspirin involved the protection of vein graft endothelium. Thus, we provide strong evidence that thrombus formation occurs before the development of neointimal lesions in vein grafts and that local aspirin treatment successfully reduces vein graft arteriosclerosis through endothelial protection, resulting in reduction of thrombosis.
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PMID:Thrombosis and neointima formation in vein grafts are inhibited by locally applied aspirin through endothelial protection. 1511 16

Currently, vascular lesions are being classified either as tumors with inherent proliferative potential or as vascular malformations with early manifestation and growth commensurate with the growth of the child. This new classification is also applicable to skeletal vascular lesions. 30% of all skeletal vascular lesions manifest in the first two decades of life, with a preponderance of malformations. They are attributed to disturbances in the complex cascade of angiogenesis and a minority may be hereditary. Multiple cutaneous vascular malformations are associated with mutations of the TIE2- and Glomulin-Genes. Vascular malformations with involvement of multiple skeletal elements may pursue an aggressive course and manifest as massive osteolysis. Among the epithelioid vascular tumours of bone, also in young patients, benign epithelioid hemangioma can be distinguished on a morphological basis from epithelioid hemangioendothelioma as an entity with low malignant potential.
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PMID:[Skeletal vascular lesions in childhood and adolescence]. 1516 77

Three insertion elements were previously found in a family of germ line-limited mobile elements, the Tlr elements, in the ciliate Tetrahymena. Each of the insertions contains an open reading frame (ORF). Sequence analysis of the deduced proteins encoded by the elements suggests that they are homing endonucleases. The genes are designated TIE1-1, TIE2-1, and TIE3-1 for Tetrahymena insertion-homing endonuclease. The endonuclease motif occupies the amino terminal half of each TIE protein. The C-terminal regions of the proteins are similar to the APETELA2 DNA binding domain of plant transcription factors. The TIE1 and TIE3 elements belong to families of repeated sequences in the germ line micronuclear genome. Comparison of the genes and the deduced proteins they encode suggests that there are at least two distinct families of homing endonuclease genes, each of which appears to be preferentially associated with a specific region of the Tlr elements. The TIE1 and TIE3 elements and their cognates undergo programmed elimination from the developing somatic macronucleus of Tetrahymena. The possible role of homing endonuclease-like genes in the DNA breakage step in developmentally programmed DNA elimination in Tetrahymena is discussed.
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PMID:Homing endonucleases encoded by germ line-limited genes in Tetrahymena thermophila have APETELA2 DNA binding domains. 1518 89

A general understanding of the molecular mechanisms underlying angiogenesis is emerging from the analysis of targeted mutations in vasculature-related genes. These analyses reveal that angiopoietin signaling through the TIE2 receptor is involved in regulating angiogenesis. Recently, we and several other groups have independently identified several molecules containing a coiled-coil domain and a fibrinogen-like domain, both of which are structurally conserved in angiopoietins. Because these molecules do not bind to the angiopoietin-specific receptor,TIE2, they have been named angiopoietin-related proteins (ARPs) or angiopoietin-like proteins (Angptls). ARPs/Angptls, which are all currently orphan ligands, also have potent activity for regulating angiogenesis as proangiogenic or antiangiogenic factors, suggesting that their receptors may be expressed on endothelial cells. In addition, ARPs/Angptls show pleiotropic effects not only on vascular cells but also on cells of other lineages, such as skin and chondrocyte cells. More recent studies have proposed that ARPs/Angptls are involved in various pathologies, such as tumor angiogenesis and metabolic diseases. To summarize the current findings relating to these proteins, we focus in this review on the functions of ARPs/Angptls as new angiogenic modulating factors in the vascular system and discuss the pleiotropic functions of ARPs/Angptls in nonvascular cell lineages.
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PMID:Angiopoietin-related/angiopoietin-like proteins regulate angiogenesis. 1529 64

A 47-year-old woman presented with multiple bluish subcutaneous nodules on the trunk and upper extremities. The histological diagnosis of a subcutaneous nodule was cavernous hemangioma. Multiple cavernous hemangiomas were also found in her cerebrum, cerebellum, and medulla oblongata on magnetic resonance imaging examination. We did not detect any mutations in the two loci of the TIE2 gene that have been reported in familial venous malformations.
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PMID:A case of multiple cavernous hemangiomas with skin and central nervous system involvement. 1567 15

CP-673,451 is a potent inhibitor of platelet-derived growth factor beta-receptor (PDGFR-beta) kinase- and PDGF-BB-stimulated autophosphorylation of PDGFR-beta in cells (IC(50) = 1 nmol/L) being more than 450-fold selective for PDGFR-beta versus other angiogenic receptors (e.g., vascular endothelial growth factor receptor 2, TIE-2, and fibroblast growth factor receptor 2). Multiple models have been used to evaluate in vivo activity of CP-673,451 and to understand the pharmacology of PDGFR-beta inhibition and the effect on tumor growth. These models include an ex vivo measure of PDGFR-beta phosphorylation in glioblastoma tumors, a sponge model to measure inhibition of angiogenesis, and multiple models of tumor growth inhibition. Inhibition of PDGFR-beta phosphorylation in tumors correlates with plasma and tumor levels of CP-673,451. A dose of 33 mg/kg was adequate to provide >50% inhibition of receptor for 4 hours corresponding to an EC(50) of 120 ng/mL in plasma at C(max). In a sponge angiogenesis model, CP-673,451 inhibited 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg (q.d. x 5, p.o., corresponding to 5.5 ng/mL at C(max)). The compound did not inhibit vascular endothelial growth factor- or basic fibroblast growth factor-induced angiogenesis at concentrations which inhibited tumor growth. The antitumor efficacy of CP-673,451 was evaluated in a number of human tumor xenografts grown s.c. in athymic mice, including H460 human lung carcinoma, Colo205 and LS174T human colon carcinomas, and U87MG human glioblastoma multiforme. Once-daily p.o. x 10 days dosing routinely inhibited tumor growth (ED(50) < or = 33 mg/kg). These data show that CP-673,451 is a pharmacologically selective PDGFR inhibitor, inhibits tumor PDGFR-beta phosphorylation, selectively inhibits PDGF-BB-stimulated angiogenesis in vivo, and causes significant tumor growth inhibition in multiple human xenograft models.
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PMID:Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451. 1570 96

Vascular morphogenesis is a vital process for embryonic development, normal physiologic conditions (e.g. wound healing) and pathological processes (e.g. atherosclerosis, cancer). Genetic studies of vascular anomalies have led to identification of critical genes involved in vascular morphogenesis. A susceptibility gene, VG5Q (formally named AGGF1), was cloned for Klippel-Trenaunay syndrome (KTS). AGGF1 encodes a potent angiogenic factor, and KTS-associated mutations enhance angiogenic activity of AGGF1, defining 'increased angiogenesis' as one molecular mechanism for the pathogenesis of KTS. Similar studies have identified other genes involved in vascular anomalies as important genes for vascular morphogenesis, including TIE2, VEGFR-3, RASA1, KRIT1, MGC4607, PDCD10, glomulin, FOXC2, NEMO, SOX18, ENG, ACVRLK1, MADH4, NDP, TIMP3, Notch3, COL3A1 and PTEN. Future studies of vascular anomaly genes will provide insights into the molecular mechanisms for vascular morphogenesis, and may lead to the development of therapeutic strategies for treating these and other angiogenesis-related diseases, including coronary artery disease and cancer.
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PMID:Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis. 1590 66

Human vascular endothelial growth factor (VEGF), angiopoietin (ANG) and tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (TIE)-2 consist of a grouping of proteins that are involved in vascular homeostasis, vascular integrity and angiogenesis. There are nine proteins in the immediate VEGF family: VEGFA, VEGFB, VEGFC, VEGFD, VEGF-3, placental growth factor (PGF), VEGF receptor (VEGFR)-1, VEGFR-2, and VEGFR-1-related. They can be stimulated by cytokines to become involved in immune responses. By using in silico tools, we were able to identify several possible analogues or homologues of VEGF, ANG and TIE-2 in invertebrates. This is the first report to show that these proteins may be conserved through evolution. These proteins may have a role in vascular maintenance and immunity. In addition, since VEGF, ANG and TIE-2 have a role in mammalian immunity that is significantly influenced by cytokines, such as IL-1, this may indicate an interaction of the vascular system and the immune system over evolutionary time.
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PMID:Evolutionary analysis of human vascular endothelial growth factor, angiopoietin, and tyrosine endothelial kinase involved in angiogenesis and immunity. 1598 40

The yolk sac and the para-aortic splanchnopleura/aorta-genital ridges-mesonephros (P-Sp/AGM) region are the main sites of haematopoietic activity in the mouse embryo at the pre-liver stage of development. By day 11.5 of gestation, the AGM region is capable of autonomous initiation and expansion of definitive haematopoietic stem cells (HSCs). By day 12.5, HSC activity in the AGM region is reduced whilst a second wave of HSCs begins to emerge in the yolk sac. We show here that HSCs emerging in both locations are marked by co-expression of the endothelial-specific marker VE-cadherin and the pan-leukocyte antigen CD45. Phenotypic characterisation using CD31, TIE2, FLK1, Ac-LDL receptors, and CD34 markers demonstrated significant similarities between this VE-cadherin+CD45+ ;double-positive' population and endothelial cells suggesting a common origin for these cells. The double-positive fraction also expressed the stem cell markers Kit, Sca1 and AA4.1. Long-term transplantation experiments demonstrated that the double-positive population, which constituted less than 0.05% of the day 11.5 AGM region and the day 12.5 yolk sac, is highly enriched for HSCs. In vitro assays showed that this population is also enriched for myeloid progenitors. During foetal liver colonization, circulating HSCs remained within the VE-cadherin+ cell fraction, although their phenotypic similarity with endothelial cells became less prominent. Upon liver colonisation the majority of HSCs downregulated VE-cadherin, expression of which was completely lost in the adult bone marrow. Partial loss of VE-cadherin expression in HSCs can be observed extra hepatically in the advanced AGM region by E12.5. Similarly, the CD34+KIT+ population in the placenta, recently identified as a reservoir of HSCs, partly lose VE-cadherin expression by E12.5. By culturing isolated E11.5 AGM region and E12.5 yolk sac we show that the developmental switch from a ;primary' VE-cadherin+CD45+ to a more ;advanced' VE-cadherin-CD45+ phenotype does not require contact of HSCs with the liver and is probably a function of developmental time.
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PMID:Progressive divergence of definitive haematopoietic stem cells from the endothelial compartment does not depend on contact with the foetal liver. 1610 75


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