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)

VEGF dependent angiogenesis is required for normal bone development and has been implicated in cancer metastasis to bone. These processes, while dependent on osteoclastic bone resorption, are reportedly mediated by endothelial cells, stromal osteoblasts, chondrocytes, and/or tumor cells. We demonstrate here that VEGF treatment of purified murine bone marrow osteoclast precursors directly enhances their survival, differentiation into mature osteoclasts, and resorptive activity. The actions of VEGF on mature osteoclasts principally involve the receptor VEGFR2 (Flk1, KDR), and the receptor signaling utilizes both the PI3-kinase-->Akt and MEK-->ERK pathways. Increased osteoclast survival and resorptive activity is correlated with VEGF-dependent phosphorylation of multiple downstream targets of activated Akt [glycogen synthase kinase, GSK-3beta; forkhead transcription factor, FKHR; and the Bcl-2 antagonist of cell death, Bad (Ser136)] and activated ERK1/2 [ribosomal S6 kinase, p90RSK; and Bad (Ser112)]. Expression of the VEGFR2 gene increases 20-fold during the 6 day in vitro differentiation of mature osteoclasts from mononuclear precursors, while alternate receptors VEGFR1 and neuropilin-1, decrease 30- and 3-fold respectively. Additionally, VEGF enhancement of osteoclast survival is diminished in cells prepared from beta3 integrin-deficient mice, thus associating VEGF signaling in osteoclasts with their attachment to extracellular matrix. Our results indicate that VEGF directly targets osteoclasts, thereby playing a novel role in bone development, angiogenesis, and tumor metastasis.
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PMID:VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and beta3-integrin. 1864 Feb 70

The human VEGF family consists of VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). The VEGF family of receptors consists of three protein-tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3) and two non-protein kinase co-receptors (neuropilin-1 and neuropilin-2). These components participate in new blood vessel formation from angioblasts (vasculogenesis) and new blood vessel formation from pre-existing vasculature (angiogenesis). Interaction between VEGFR1 and VEGFR2 or VEGFR2 and VEGFR3 alters receptor tyrosine phosphorylation.
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PMID:VEGF receptor protein-tyrosine kinases: structure and regulation. 1868 Jul 22

Angiogenesis is a key process in the endometrium which undergoes dramatic changes during the menstrual cycle. Molecules such as vascular endothelial growth factor (VEGF), acting via two tyrosine kinase family receptors (VEGFR1 [Flt-1] and VEGFR2 [KDR/Flk-1]), are potent modulators of angiogenesis and vascular remodelling in the endometrium. Recently, neuropilin-1 (NRP-1) was shown to be expressed in endothelial cells binding VEGF(165) and therewith enhancing the binding of VEGF(165) to VEGFR2. This suggests that NRP-1, in addition to the known VEGF receptors, may play an important role in VEGF-induced angiogenesis. In this study, the expression of NRP-1 in the cycling human endometrium has been investigated by reverse transcription (RT)-polymerase chain reaction (RT-PCR), semi-quantitative competitive RT-PCR (RT-cPCR) and immunohistochemical staining. NRP-1 was expressed in all 32 endometrium samples throughout the menstrual cycle. However, samples from the proliferative phase showed significantly higher expression levels of NRP-1 mRNA compared to samples from the secretory phase (t/c-ratio 2.13 vs. 0.84, p<0.05). Immunohistochemistry confirmed the results showing increased NRP-1 staining in vascular endothelium, glandular epithelium and stromal cells of the proliferative phase endometrium. This study demonstrates mRNA and protein expression of NRP-1 in human endometrium samples throughout the menstrual cycle. The enhanced expression of NRP-1 in the proliferative phase suggests that it may participate in hormonally regulated changes of endometrial angiogenesis, preparing the endometrium for the implantation of an embryo. NRP-1 expression might act as a co-factor for VEGF(165) enhancing the angiogenic stimulus.
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PMID:Expression of the vascular endothelial growth factor receptor neuropilin-1 in the human endometrium. 1899 1

Vascular endothelial growth factor (VEGF) signal transduction through the cell surface receptors VEGFR1 and VEGFR2 regulates angiogenesis-the growth of new capillaries from preexistent microvasculature. Soluble VEGF receptor-1 (sVEGFR1), a nonsignaling truncated variant of VEGFR1, has been postulated to inhibit angiogenic signaling via direct sequestration of VEGF ligands or dominant-negative heterodimerization with surface VEGFRs. The relative contributions of these two mechanisms to sVEGFR1's purported antiangiogenic effects in vivo are currently unknown. We previously developed a computational model for predicting the compartmental distributions of VEGF and sVEGFR1 throughout the healthy human body by simulating the molecular interaction networks of the VEGF ligand-receptor system as well as intercompartmental macromolecular biotransport processes. In this study, we decipher the dynamic processes that led to our prior prediction that sVEGFR1, through its ligand trapping mechanism alone, does not demonstrate significant steady-state antiangiogenic effects. We show that sVEGFR1-facilitated tissue-to-blood shuttling of VEGF accounts for a counterintuitive and drastic elevation in plasma free VEGF concentrations after both intramuscular and intravascular sVEGFR1 infusion. While increasing intramuscular VEGF production reduces free sVEGFR1 levels through increased VEGF-sVEGFR1 complex formation, we demonstrate a competing and opposite effect in which increased VEGF occupancy of neuropilin-1 (NRP1) and the corresponding reduction in NRP1 availability for internalization of sVEGFR1 unexpectedly increases free sVEGFR1 levels. In conclusion, dynamic intercompartmental transport processes give rise to our surprising prediction that VEGF trapping alone does not account for sVEGFR1's antiangiogenic potential. sVEGFR1's interactions with cell surface receptors such as NRP1 are also expected to affect its molecular interplay with VEGF.
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PMID:Computational kinetic model of VEGF trapping by soluble VEGF receptor-1: effects of transendothelial and lymphatic macromolecular transport. 1935 8

Vascular endothelial growth factor (VEGF), through its activation of cell surface receptor tyrosine kinases including VEGFR1 and VEGFR2, is a vital regulator of stimulatory and inhibitory processes that keep angiogenesis--new capillary growth from existing microvasculature--at a dynamic balance in normal physiology. Soluble VEGF receptor-1 (sVEGFR1)--a naturally-occurring truncated version of VEGFR1 lacking the transmembrane and intracellular signaling domains--has been postulated to exert inhibitory effects on angiogenic signaling via two mechanisms: direct sequestration of angiogenic ligands such as VEGF; or dominant-negative heterodimerization with surface VEGFRs. In pre-clinical studies, sVEGFR1 gene and protein therapy have demonstrated efficacy in inhibiting tumor angiogenesis; while in clinical studies, sVEGFR1 has shown utility as a diagnostic or prognostic marker in a widening array of angiogenesis-dependent diseases. Here we developed a novel computational multi-tissue model for recapitulating the dynamic systemic distributions of VEGF and sVEGFR1. Model features included: physiologically-based multi-scale compartmentalization of the human body; inter-compartmental macromolecular biotransport processes (vascular permeability, lymphatic drainage); and molecularly-detailed binding interactions between the ligand isoforms VEGF(121) and VEGF(165), signaling receptors VEGFR1 and VEGFR2, non-signaling co-receptor neuropilin-1 (NRP1), as well as sVEGFR1. The model was parameterized to represent a healthy human subject, whereupon we investigated the effects of sVEGFR1 on the distribution and activation of VEGF ligands and receptors. We assessed the healthy baseline stability of circulating VEGF and sVEGFR1 levels in plasma, as well as their reliability in indicating tissue-level angiogenic signaling potential. Unexpectedly, simulated results showed that sVEGFR1 - acting as a diffusible VEGF sink alone, i.e., without sVEGFR1-VEGFR heterodimerization--did not significantly lower interstitial VEGF, nor inhibit signaling potential in tissues. Additionally, the sensitivity of plasma VEGF and sVEGFR1 to physiological fluctuations in transport rates may partially account for the heterogeneity in clinical measurements of these circulating angiogenic markers, potentially hindering their diagnostic reliability for diseases.
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PMID:A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap. 1935 13

Sympathetic nerve activity regulates blood pressure by altering peripheral vascular resistance. Variations in vascular sympathetic innervation suggest that vascular-derived cues promote selective innervation of particular vessels during development. As axons extend towards peripheral targets, they migrate along arterial networks following gradients of guidance cues. Collective ratios of these gradients may determine whether axons grow towards and innervate vessels or continue past non-innervated vessels towards peripheral targets. Utilizing directed neurite outgrowth in a three-dimensional (3D) co-culture, we observed increased axon growth from superior cervical ganglion explants (SCG) towards innervated compared to non-innervated vessels, mediated in part by vascular endothelial growth factor (VEGF-A) and Semaphorin3A (Sema3A) which both signal via neuropilin-1 (Nrp1). Exogenous VEGF-A, delivered by high-expressing VEGF-A-LacZ vessels or by rhVEGF-A/alginate spheres, increased sympathetic neurite outgrowth while exogenous rhSema3A/Fc decreased neurite outgrowth. VEGF-A expression is similar between the innervated and non-innervated vessels examined. Sema3A expression is higher in non-innervated vessels. Spatial gradients of Sema3A and VEGF-A may promote differential Nrp1 binding. Vessels expressing high levels of Sema3A favor Nrp1-PlexinA1 signaling, producing chemorepulsive cues limiting sympathetic neurite outgrowth and vascular innervation; while low Sema3A expressing vessels favor Nrp1-VEGFR2 signaling providing chemoattractive cues for sympathetic neurite outgrowth and vascular innervation.
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PMID:VEGF-A and Semaphorin3A: modulators of vascular sympathetic innervation. 1963 37

Epithelial ovarian cancer (EOC) is a serious gynecological cancer and there may be an increased risk of developing EOC in women with metabolic disruptions such as diabetes-related hyperglycemia, obesity or high glycemic load. Upregulation of vascular endothelial growth factor (VEGF) in ischemic conditions (e.g. hypoxia, hypoglycemia) induces tumor angiogenesis. We previously showed that EOC cells employ an autocrine VEGF/VEGFR2 signaling loop. Here we demonstrate the influence of glucose levels on VEGF and its receptors in the human EOC lines OVCAR-3 and CAOV-3. Glucose (but not pyruvate) deprivation induced significant increase in VEGF transcription and secretion, but a rapid reduction in VEGFR2 protein synthesis and glycosylation, combined with a reduction in co-receptor neuropilin-1 (NRP-1) protein levels. In contrast, mRNA for KDR and NRP-1 was increased upon glucose depletion suggesting a mechanism of feed back upon protein reduction. The addition of the proteosome inhibitor epoxomycin restored VEGFR2 under glucose free conditions, suggesting degradation as the main mechanism of VEGFR2 reduction and transcriptional activation through the unfolded protein response (UPR) which was activated in glucose-starved cells through the upregulation of the Endoplasmic reticulum chaperon GRP-78. Our finding that glucose can regulate VEGF/VEGFR2 levels suggests that initiation and/or progression of ovarian surface epithelial cells towards a neoplastic phenotype might be modulated by dietary conditions, and that a patient's metabolic status may alter the effectiveness of the known anti-angiogenic therapies. This information provides opportunities to explore the biology of EOC progression and improve our understanding of the mechanistic insight of this interesting regulatory effect.
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PMID:Glucose is a key regulator of VEGFR2/KDR in human epithelial ovarian carcinoma cells. 1978 46

Both vascular endothelial growth factor receptors (VEGFR) and integrins are major regulators of VEGF-induced angiogenesis. Previous work has shown that beta3 integrin can regulate negatively VEGFR2 expression. Here we show that beta3 integrin can regulate negatively VEGF-mediated angiogenesis by limiting the interaction of the co-receptor NRP1 (neuropilin-1) with VEGFR2. In the presence of alphav beta3 integrin, NRP1 contributed minimally to VEGF-induced angiogenic processes in vivo, ex vivo, and in vitro. Conversely, when beta3 integrin expression is absent or low or its function is blocked with RGD-mimetic inhibitors, VEGF-mediated responses became NRP1-dependent. Indeed, combined inhibition of beta3 integrin and NRP1 decreased VEGF-mediated angiogenic responses further than individual inhibition of these receptors. We also show that alphav beta3 integrin can associate with NRP1 in a VEGF-dependent fashion. Our data suggest that beta3 integrin may, in part, negatively regulate VEGF signaling by sequestering NRP1 and preventing it from interacting with VEGFR2.
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PMID:Alphav beta3 integrin limits the contribution of neuropilin-1 to vascular endothelial growth factor-induced angiogenesis. 1983 59

Vascular endothelial growth factor (VEGF) is a potent cytokine that binds to specific receptors on the endothelial cells lining blood vessels. The signaling cascade triggered eventually leads to the formation of new capillaries, a process called angiogenesis. Distributions of VEGF receptors and VEGF ligands are therefore crucial determinants of angiogenic events and, to our knowledge, no quantification of abluminal vs. luminal receptors has been performed. We formulate a molecular-based compartment model to investigate the VEGF distribution in blood and tissue in humans and show that such quantification would lead to new insights on angiogenesis and VEGF-dependent diseases. Our multiscale model includes two major isoforms of VEGF (VEGF(121) and VEGF(165)), as well as their receptors (VEGFR1 and VEGFR2) and the non-signaling co-receptor neuropilin-1 (NRP1). VEGF can be transported between tissue and blood via transendothelial permeability and the lymphatics. VEGF receptors are located on both the luminal and abluminal sides of the endothelial cells. In this study, we analyze the effects of the VEGF receptor localization on the endothelial cells as well as of the lymphatic transport. We show that the VEGF distribution is affected by the luminal receptor density. We predict that the receptor signaling occurs mostly on the abluminal endothelial surface, assuming that VEGF is secreted by parenchymal cells. However, for a low abluminal but high luminal receptor density, VEGF binds predominantly to VEGFR1 on the abluminal surface and VEGFR2 on the luminal surface. Such findings would be pertinent to pathological conditions and therapies related to VEGF receptor imbalance and overexpression on the endothelial cells and will hopefully encourage experimental receptor quantification for both luminal and abluminal surfaces on endothelial cells.
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PMID:The presence of VEGF receptors on the luminal surface of endothelial cells affects VEGF distribution and VEGF signaling. 2004 Dec 9

Using human MSCs (mesenchymal stem cells) lacking VEGF (vascular endothelial growth factor) receptors, we show that the pro-angiogenic receptor neuropilin-1 associates with phosphorylated PDGFRs [PDGF (platelet-derived growth factor) receptors], thereby regulating cell signalling, migration, proliferation and network assembly. Neuropilin-1 co-immunoprecipitated and co-localized with phosphorylated PDGFRs in the presence of growth factors. Neuropilin-1 knockdown blocked PDGF-AA-induced PDGFRalpha phosphorylation and migration, reduced PDGF-BB-induced PDGFRbeta activation and migration, blocked VEGF-A activation of both PDGFRs, and attenuated proliferation. Neuropilin-1 prominently co-localized with both PDGFRs within MSC networks assembled in Matrigel and in the chorioallantoic membrane vasculature microenvironment, and its knockdown grossly disrupted network assembly and decreased PDGFR signalling. Thus neuropilin-1 regulates MSCs by forming ligand-specific receptor complexes that direct PDGFR signalling, especially the PDGFRalpha homodimer. This receptor cross-talk may control the mobilization of MSCs in neovascularization and tissue remodelling.
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PMID:Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells. 2010 35


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