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)

The acquisition of cell type specific properties in the spinal cord is a process of a sequential restriction in developmental potential. Multipotent neuroepithelial stem cells (NEP cells) can give rise to all the major cell types in the central nervous system. The generation of these multiple cell types occurs via the generation of intermediate precursor cells, which are restricted in their differentiation potential, but are still able to give rise to more than one cell type. These intermediate precursor cells are different from NEP cells and are different from each other. We have identified neuronal restricted precursor cells (NRP's) which can only generate neurons but no longer glial cells and glial restricted precursor cells (GRP's), which give rise to glial cells but not to neurons. These intermediate precursor cells can be purified and expanded in vitro and might offer a new tool for gene discovery, drug screening and transplantation approaches.
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PMID:Cell differentiation in the embryonic mammalian spinal cord. 1033 88

Vascular endothelial growth factor (VEGF-A) is an inducer of endothelial cell (EC) proliferation, migration, and synthesis of inflammatory agents such as platelet-activating factor (PAF). Recently, neuropilin-1 (NRP-1) has been described as a coreceptor of KDR which potentiates VEGF-A activity. However, the role of NRP-1 in numerous VEGF-A activities remains unclear. To assess the contribution of NRP-1 to VEGF-A mediated EC proliferation, migration, and PAF synthesis, we used porcine aortic EC (PAEC) recombinantly expressing Flt-1, NRP-1, KDR or KDR and NRP-1. Cells were stimulated with VEGF-A, which binds to Flt-1, KDR and NRP-1, and VEGF-C, which binds to KDR only. VEGF-A was 12.4-fold more potent than VEGF-C in inducing KDR phosphorylation in PAEC-KDR. VEGF-A and VEGF-C showed similar potency to mediate PAEC-KDR proliferation, migration, and PAF synthesis. On PAEC-KDR/NRP-1, VEGF-A was 28.6-fold more potent than VEGF-C in inducing KDR phosphorylation and PAEC-KDR/NRP-1 proliferation (1.3-fold), migration (1.7-fold), and PAF synthesis (4.6-fold). These results suggest that cooperative binding of VEGF-A to KDR and NRP-1 enhances KDR phosphorylation and its biological activities. Similar results were obtained with bovine aortic EC that endogenously express both KDR and NRP-1 receptors. In contrast, stimulation of PAEC-Flt-1 and PAEC-NRP-1 with VEGF-A or VEGF-C did not induce proliferation, migration, or PAF synthesis. In conclusion, the presence of NRP-1 on EC preferentially increases KDR activation by VEGF-A as well as KDR-mediated biological activities, and may elicit novel intracellular events. On the other hand, VEGF-A and VEGF-C have equipotent biological activities on EC in absence of NRP-1.
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PMID:Relative effects of VEGF-A and VEGF-C on endothelial cell proliferation, migration and PAF synthesis: Role of neuropilin-1. 1196 3

Recent findings implied that the progression of hematologic malignancies, like that of solid tumors, is dependent on neovascularization. Recent studies on patients with acute myeloid leukemia (AML) showed increased levels of leukocyte-associated vascular endothelial growth factor (VEGF) and neovascularization of the bone marrow. Murine (32D, M1) and human (HEL, U937, and UKE-1) leukemic cell lines and freshly isolated leukemic cells were analyzed for the expression of VEGF and VEGF receptor mRNA. The expression of VEGF and VEGF receptors KDR and neuropilin-1 (NRP-1) was detected in these cells. In a murine chloroma model, delivery of VEGF(165) using microencapsulation technology resulted in enhanced tumor growth and vascularization, whereas treatment with a VEGF antagonist soluble NRP-1 (sNRP-1) inhibited tumor angiogenesis and growth. In a systemic leukemia model, survival of mice injected with adenovirus (Ad) encoding for Fc-sNRP-1 (sNRP-1 dimer) was significantly prolonged as compared with mice injected with Ad-LacZ. Further analyses showed a reduction in circulating leukemic cells and infiltration of liver and spleen as well as bone marrow neovascularization and cellularity. Taken together, these results demonstrate that angiogenic factors such as VEGF promote AML progression in vivo. The use of VEGF antagonists as an antiangiogenesis approach offers a potential treatment for AML. Finally, our novel in vivo drug delivery model may be useful for testing the activities of other peptide antiangiogenic factors.
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PMID:In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo. 1245 80

Neuropilin-1 (NRP-1) has been found to be expressed by endothelial cells and tumor cells as an isoform-specific receptor for vascular permeability factor/vascular endothelial growth factor (VEGF). Previous studies were mainly focused on the extracellular domain of NRP-1 that can bind to VEGF165 and, thus, enables NRP-1 to act as a co-receptor for VEGF165, which enhances its binding to VEGFR-2 and its bioactivity. However, the exact functional roles and related signaling mechanisms of NRP-1 in angiogenesis are not well understood. In this study we constructed a chimeric receptor, EGNP-1, by fusing the extracellular domain of epidermal growth factor receptor to the transmembrane and intracellular domains of NRP-1 and transduced it into HUVECs with a retroviral expression vector. We observed that NRP-1/EGNP-1 mediates ligand-stimulated migration of human umbilical vein endothelial cells (HUVECs) but not proliferation. Our results show that NRP-1 alone can mediate HUVEC migration through its intracellular domain, and its C-terminal three amino acids (SEA-COOH) are essential for the process. We demonstrate that phosphatidylinositol 3-kinase inhibitor Ly294002 and the p85 dominant negative mutant can block NRP-1-mediated HUVEC migration. NRP-1-mediated migration can be significantly reduced by overexpression of the dominant negative mutant of RhoA (RhoA-19N). In addition, Gq family proteins and Gbetagamma subunits are also required for NRP-1-mediated HUVEC migration. These results show for the first time that NRP-1 can independently promote cell signaling in endothelial cells and also demonstrate the importance of last three amino acids of NRP-1 for its function.
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PMID:Neuropilin-1-mediated vascular permeability factor/vascular endothelial growth factor-dependent endothelial cell migration. 1451 74

Nearly all brain tumors develop following the progressive accumulation of genetic alterations of oncogenes and tumor suppressor genes (such as p53 and retinoblastoma protein). Furthermore, aberrations in the nuclear matrix often contribute to genomic instabilities and the development of cancer. We have previously shown that nuclear-restricted protein/brain (NRP/B), a member of the BTB/Kelch repeat family, is a nuclear matrix protein normally expressed in neurons but not in astrocytes, and that it is an early and specific marker of neurons during the development of the central nervous system. Here, we show aberrant expression of NRP/B in human brain tissues. NRP/B is expressed in the cytoplasm of human brain tumor cells (glioblastoma, GBM) arising from astrocytes. NRP/B mutations (13 mutations in the Kelch domains, two in the intervening sequence (IVS) domain and two in the BTB domain) were detected in brain tumor cell lines (A-172, CCF-STTG1, SK-N-SH and U87-MG) and in primary human malignant GBM tissues (eight samples). More importantly, we found that NRP/B mutants, but not wild-type (wt) NRP/B, increased the activation of ERK and consequently promoted cell proliferation, attenuated caspase activation and suppressed the cellular apoptosis induced by the stressful stimulus cisplatin (10 microM). These events were observed to occur via a p53-mediated pathway. In addition, while wt NRP/B was associated with actin, mutations in the Kelch domains of NRP/B led to its reduced binding affinity to actin. Thus, alterations and gene mutations within the NRP/B gene may contribute to brain tumorigenesis by promoting cell proliferation, suppressing apoptosis and by affecting nuclear cytoskeleton dynamics.
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PMID:Genetic alterations of the NRP/B gene are associated with human brain tumors. 1520 78

Destruction of the neovasculature is essential for efficient tumor eradication by photodynamic therapy (PDT). Since the over-expression of receptors for vascular endothelial growth factor (VEGF) is correlated with tumor angiogenesis and subsequent growth, we conjugated a photosensitizer (5-(4-carboxyphenyl)-10,15,20-triphenyl-chlorin, TPC), via a spacer (6-aminohexanoic acid, Ahx), to a VEGF receptor-specific heptapeptide (ATWLPPR). ATWLPPR and TPC-Ahx-ATWLPPR bound exclusively to neuropilin-1 (NRP-1) recombinant chimeric protein (IC50=19 and 171 microM, respectively) but were devoid of affinity for VEGF receptor type 2 (VEGFR-2, KDR), to which ATWLPPR was initially thought to bind. TPC-Ahx-ATWLPPR was incorporated up to 25-fold more in human umbilical vein endothelial cells (HUVEC) than TPC over a 24-h period, and the addition of 8 mM ATWLPPR induced a significant decrease of this uptake (P<0.05), corroborating a receptor-mediated incorporation. Slightly less cytotoxic in the dark, TPC-Ahx-ATWLPPR exhibited enhanced in vitro photodynamic activity (10.4-fold), compared to TPC. Pharmacokinetic analysis in nude mice xenografted with U87 human malignant glioma cells revealed relevant tumor levels as soon as 1 h after intravenous injection of TPC-Ahx-ATWLPPR, and a rapid elimination from the blood compartment. Moreover, TPC-Ahx-ATWLPPR was not degraded in vivo up to 2 h after intravenous injection. Taken together, our results demonstrate that TPC-Ahx-ATWLPPR is a much more potent photosensitizer in vitro than TPC, in NRP-1-expressing cells. Thus, it may efficiently potentiate the vascular effect of PDT in vivo.
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PMID:A peptide competing with VEGF165 binding on neuropilin-1 mediates targeting of a chlorin-type photosensitizer and potentiates its photodynamic activity in human endothelial cells. 1642 22

Initially, it was thought that there was no intracellular signaling mediated by NRP-1 alone in response to its ligands. However, the emerging data from our group as well as others suggest that the signaling through NRP-1 actually promotes angiogenesis and is mediated through its C-terminal domain and downstream molecules such as phosphoinositide 3-kinase. Hence, understanding the signal transduction pathways mediated by NRP-1 and identification of its downstream molecules are of importance. By using both in vivo zebrafish model and in vitro tissue culture system, we have shown that the C-terminal three amino acids of NRP-1 (SEA-COOH) are required for NRP-1-mediated angiogenesis. Furthermore, knocking down of RGS-GAIP-interacting protein C terminus (GIPC) in zebrafish, which is associated with C-terminal domain of NRP-1, exhibits similar vasculature phenotypes to those from NRP-1 null. Specific and effective silencing of GIPC in vascular endothelium results in inhibition of NRP-1-mediated migration. In both cases as described, PDZ domain of GIPC is responsible for its function. Taken together, our data suggest a novel role of GIPC in angiogenesis and vessel formation and also support our hypothesis that NRP-1 can facilitate downstream signaling to promote angiogenesis through GIPC.
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PMID:C terminus of RGS-GAIP-interacting protein conveys neuropilin-1-mediated signaling during angiogenesis. 1675 45

Neuropilin-1 (NRP-1), a non-tyrosine kinase receptor of vascular endothelial growth factor-165 (VEGF165), was found expressed on endothelial and some tumor cells. Since its overexpression is correlated with tumor angiogenesis and progression, the targeting of NRP-1 could be a potential anti-cancer strategy. To explore this hypothesis, we identified a peptide inhibiting the VEGF165 binding to NRP-1 and we tested whether it was able to inhibit tumor growth and angiogenesis. To prove the target of peptide action, we assessed its effects on binding of radiolabeled VEGF165 to recombinant receptors and to cultured cells expressing only VEGFR-2 (KDR) or NRP-1. Antiangiogenic activity of the peptide was tested in vitro in tubulogenesis assays and in vivo in nude mice xenotransplanted in fat-pad with breast cancer MDA-MB-231 cells. Tumor volumes, vascularity and proliferation indices were determined. The selected peptide, ATWLPPR, inhibited the VEGF165 binding to NRP-1 but not to tyrosine kinase receptors, VEGFR-1 (flt-1) and KDR; nor did it bind to heparin. It diminished the VEGF-induced human umbilical vein endothelial cell proliferation and tubular formation on Matrigel and in co-culture with fibroblasts. Administration of ATWLPPR to nude mice inhibited the growth of MDA-MB-231 xenografts, and reduced blood vessel density and endothelial cell area but did not alter the proliferation indices of the tumor. In conclusion, ATWLPPR, a previously identified KDR-interacting peptide, was shown to inhibit the VEGF165 interactions with NRP-1 but not with KDR and to decrease the tumor angiogenesis and growth, thus validating, in vivo, NRP-1 as a possible target for antiangiogenic and antitumor agents.
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PMID:Antiangiogenic and antitumor activities of peptide inhibiting the vascular endothelial growth factor binding to neuropilin-1. 1695 72

Vascular endothelial growth factor (VEGF) is produced in neoplastic cells in various myeloid neoplasms and may act as an autocrine growth-regulator. We have examined the expression of five VEGF receptors (VEGR1/Flt-1, VEGFR2/KDR, Flt-4, neuropilin-1 = NRP-1, NRP-2) in leukemic cells obtained from patients with acute myeloid leukemia (n = 28), chronic myeloid leukemia (n = 14), chronic eosinophilic leukemia (n = 3), chronic myelomonocytic leukemia (n = 9), or mast cell leukemia/systemic mastocytosis (n = 3) as well as in respective cell lines. Expression of VEGFR mRNA was analyzed by RT-PCR, and expression of VEGFR protein by immunocytochemistry. In most patients, leukemic cells expressed NRP-1 mRNA and NRP-2 mRNA independent of the type of disease. By contrast, transcripts for Flt-1, KDR, and Flt-4 were expressed variably without a clear correlation to the type of leukemia. Expression of VEGF receptors was also demonstrable at the protein level in all cases tested. In conclusion, neoplastic cells in myeloid leukemias frequently express VEGFR including NRP-1 and NRP-2.
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PMID:Myeloid leukemias express a broad spectrum of VEGF receptors including neuropilin-1 (NRP-1) and NRP-2. 1791 67

Vascular smooth muscle cells (SMCs), one of the major cell types of the vascular wall, play a critical role in the process of angiogenesis under both physiological and pathophysiological conditions, including the cancer microenvironment. Previous studies have shown that VEGF-A 165 augments vascular SMC migration via VEGFR2 (KDR/Flk1) pathways. In this study, we found that VEGF-A 165 (recombinant protein or breast tumor cell-secreted) is also capable of inducing migration of VEGFR2-negative human aortic smooth muscle cells (hAOSMCs), and this induction is mediated through a molecular cross-talk of neuropilin-1 (NRP-1), VEGFR1 (Flt-1), and phosphoinositide 3-kinase (PI3K)/Akt signaling kinase. We found that VEGF-A 165 induces hAOSMC migration parallel with the induction of NRP-1 and VEGFR1 expressions and their associations along with the activation of PI3K/Akt. Neutralization of VEGF action by its antibody or inhibition of VEGF-induced PI3K/Akt kinase activation by wortmannin, a PI3K/Akt specific inhibitor, results in inhibition of VEGF-induced hAOSMC migration. Moreover, RNAi-mediated elimination of the NRP-1 expression or blocking of the activity of VEGFR1 by its antibody in hAOSMCs impairs the VEGF-A 165-induced migration of these cells as well as activation of PI3K/Akt kinase. Collectively, these results establish, for the first time, a mechanistic link among VEGF-A 165, NRP-1, VEGFR1, and PI3K/Akt in the regulation of migration of human vascular smooth muscle cells that eventually could be involved in the angiogenic switch.
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PMID:VEGF-A165 induces human aortic smooth muscle cell migration by activating neuropilin-1-VEGFR1-PI3K axis. 1828 15


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