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)

Angiogenesis is a multistep complex phenomenon critical for several inflammatory and neoplastic disorders. Basophils, normally confined to peripheral blood, can infiltrate the sites of chronic inflammation. In an attempt to obtain insights into the mechanism(s) underlying human basophil chemotaxis and its role in inflammation, we have characterized the expression and function of vascular endothelial growth factors (VEGFs) and their receptors in these cells. Basophils express mRNA for three isoforms of VEGF-A (121, 165, and 189) and two isoforms of VEGF-B (167 and 186). Peripheral blood and basophils in nasal polyps contain VEGF-A localized in secretory granules. The concentration of VEGF-A in basophils was 144.4 +/- 10.8 pg/10(6) cells. Immunologic activation of basophils induced the release of VEGF-A. VEGF-A (10-500 ng/ml) induced basophil chemotaxis. Supernatants of activated basophils induced an angiogenic response in the chick embryo chorioallantoic membrane that was inhibited by an anti-VEGF-A Ab. The tyrosine kinase VEGFR-2 (VEGFR-2/KDR) mRNA was expressed in basophils. These cells also expressed mRNA for the soluble form of VEGFR-1 and neuropilin (NRP)1 and NRP2. Flow cytometric analysis indicated that basophils express epitopes recognized by mAbs against the extracellular domains of VEGFR-2, NRP1, and NRP2. Our data suggest that basophils could play a role in angiogenesis and inflammation through the expression of several forms of VEGF and their receptors.
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PMID:Expression and functions of the vascular endothelial growth factors and their receptors in human basophils. 1708 51

We have previously established an ovariectomized (OVX) ewe model to study how steroid removal and replacement affects uterine blood vessel and tissue growth. Using this model, endometrial expression of mRNA for 14 angiogenic factors (7 genes and their respective receptors) in caruncular (CAR) and intercaruncular (ICAR) endometrium were evaluated by quantitative real time RT-PCR at 0 (control), 2, 4, 8, 16, or 24 h after treating OVX ewes with an estradiol-17beta (E2) implant. In CAR and ICAR, compared to 0 h, the mRNA expression of vascular endothelial growth factor (VEGF), VEGF receptor (R)1, soluble guanylate cyclase (GUCY1B3; the R for nitric oxide [NO]), hypoxia inducible factor (HIF)1alpha, and placental growth factor (PlGF) increased by 4 h after E2-treatment, but basic fibroblast growth factor (FGF2), endothelial NO synthase (NOS3), angiopoietin (ANGPT)1, ANGPT2, ANGPT receptor Tie2 by 2 h after E2. Expression of mRNA for FGFR2 IIIc was increased at 2 h by E2-treatment in ICAR, but not in CAR. By contrast, expression of neuropilin (NP)1 mRNA was increased at 2 h in CAR, but not ICAR. The mRNA expression of VEGF, FGF2, HIF1 alpha, and PlGF was positively correlated with mRNA expression of NOS3, VEGFR1, and Tie2 suggesting some E2-stimulated interactions between these factors in promoting blood vessel growth. Thus, several major angiogenic factors and their receptors are increased within hours after E2-treatment, which indicates that E2 plays a role in regulation of angiogenesis in the uterus. By using the OVX ewe model, we may begin to understand the molecular basis of E2 effects on angiogenesis in the endometrium and, eventually, how angiogenesis is regulated in normal versus pathological conditions.
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PMID:Effects of estradiol-17beta on expression of mRNA for seven angiogenic factors and their receptors in the endometrium of ovariectomized (OVX) ewes. 1752 46

During bone growth, development, and remodeling, angiogenesis as well as osteogenesis are closely associated processes, sharing some essential mediators. Vascular endothelial growth factor (VEGF) was initially recognized as the best-characterized endothelial-specific growth factor, which increased vascular permeability and angiogenesis, and it is now apparent that this cytokine regulates multiple biological functions in the endochondral ossification of mandibular condylar growth, as well as long bone formation. The complexity of VEGF biology is paralleled by the emerging complexity of interactions between VEGF ligands and their receptors. This narrative review summarizes the family of VEGF-related molecules, including 7 mammalian members, namely, VEGF, placenta growth factor (PLGF), and VEGF-B, -C, -D, -E, and -F. The biological functions of VEGF are mediated by at least 3 corresponding receptors: VEGFR-1/Flt-1, VEGFR-2/Flk-1, VEGFR-3/Flt-4 and 2 co-receptors of neuropilin (NRP) and heparan sulfate proteoglycans (HSPGs). Current findings on endochondral ossification are also discussed, with emphasis on VEGF-A action in osteoblasts, chondroblasts, and chondroclasts/osteoclasts and regulatory mechanisms involving oxygen tension, and some growth factors and hormones. Furthermore, the therapeutic implications of recombinant VEGF-A protein therapy and VEGF-A gene therapy are evaluated. Abbreviations used: VEGF, Vascular endothelial growth factor; PLGF, placenta growth factor; NRP, neuropilin; HSPGs, heparan sulfate proteoglycans; FGF, fibroblast growth factor; TGF, transforming growth factor; HGF, hepatocyte growth factor; TNF, tumor necrosis factor; ECM, extracellular matrix; RTKs, receptor tyrosine kinases; ERK, extracellular signal kinases; HIF, hypoxia-inducible factor.
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PMID:VEGF: an essential mediator of both angiogenesis and endochondral ossification. 1789 Jun 69

Vascular endothelial growth factor C (VEGF-C) is a lymphangiogenic factor over-expressed in highly metastatic, cyclooxygenase (COX)-2 expressing breast cancer cells. We tested the hypothesis that tumour-derived VEGF-C may play an autocrine role in metastasis by promoting cellular motility through one or more VEGF-C-binding receptors VEGFR-2, VEGFR-3, neuropilin (NRP)-1, NRP-2, and integrin alpha9beta1. We investigated the expression of these receptors in several breast cancer cell lines (MDA-MB-231, Hs578T, SK-BR-3, T-47D, and MCF7) and their possible requirement in migration of two VEGF-C-secreting, highly metastatic lines MDA-MB-231 and Hs578T. While cell lines varied significantly in their expression of above VEGF-C receptors, migratory activity of MDA-MB-231 and Hs578T cells was linked to one or more of these receptors. Depletion of endogenous VEGF-C by treatments with a neutralising antibody, VEGF-C siRNA or inhibitors of Src, EGFR/Her2/neu and p38 MAP kinases which inhibited VEGF-C production, inhibited cellular migration, indicating the requirement of VEGF-C for migratory function. Migration was differentially attenuated by blocking or downregulation of different VEGF-C receptors, for example treatment with a VEGFR-2 tyrosine kinase inhibitor, NRP-1 and NRP-2 siRNA or alpha9beta1 integrin antibody, indicating the participation of one or more of the receptors in cell motility. This novel role of tumour-derived VEGF-C indicates that breast cancer metastasis can be promoted by coordinated stimulation of lymphangiogenesis and enhanced migratory activity of breast cancer cells.
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PMID:Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells. 1791 47

Stanniocalcin-1 (STC-1) is a glycoprotein hormone originally identified as a regulator of calcium and phosphate homeostasis in bony fish. Up-regulation of the mammalian homolog in numerous gene profiling studies of angiogenesis and vascular endothelial growth factor-A (VEGF-A(165))-regulated gene expression, suggests that regulation of this factor may be a key feature of the angiogenic response. Here we investigated the mechanisms mediating VEGF-A(165)-induced STC-1 gene expression in human endothelial cells. VEGF-A(165), acting via VEGFR2/KDR, induced STC-1 through de novo transcription, mediated primarily via intracellular protein kinase C (PKC)- and extracellular signal-regulated protein kinase (ERK)-dependent pathways. VEGF-A(165)-induced STC-1 mRNA expression was synergistically enhanced up to 2-fold by co-treatment with FGF-2, in a mechanism dependent on VEGFR2/KDR and FGFR1. Production of STC-1 protein by endothelial cells was also induced by VEGF-A(165) and synergistically enhanced by co-treatment with FGF-2. Synergism between VEGF-A(165) and FGF-2 was mediated via a novel neuropilin-1 (NP-1)-dependent mechanism, as indicated by the complete inhibition of synergism with either EG3287, a specific neuropilin antagonist, or siRNA-mediated NP-1 knockdown, and by the inability of the VEGF-A(121) isoform to synergise with FGF-2. Surprisingly, we found that NP-1 knockdown also markedly reduced KDR expression in HUVECs, and enhanced the VEGF-A(165)-induced reduction in KDR expression resulting from receptor-mediated endocytosis. These findings support a role for NP-1 in mediating synergistic effects between VEGF-A(165) and FGF-2, which may occur in part through a contribution of NP-1 to KDR stability.
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PMID:Vascular endothelial growth factor regulates stanniocalcin-1 expression via neuropilin-1-dependent regulation of KDR and synergism with fibroblast growth factor-2. 1816 91

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

Vascular endothelial growth factor (VEGF)-A and the VEGF receptors are critical for regulating angiogenesis during development and homeostasis and in pathological conditions, such as cancer and proliferative retinopathies. Most effects of VEGF-A are mediated by the VEGFR2 and its coreceptor, neuropilin (NRP)-1. Here, we show that VEGFR2 is shed from cells by the metalloprotease disintegrin ADAM17, whereas NRP-1 is released by ADAM10. VEGF-A enhances VEGFR2 shedding by ADAM17 but not shedding of NRP-1 by ADAM10. VEGF-A activates ADAM17 via the extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase pathways, thereby also triggering shedding of other ADAM17 substrates, including tumor necrosis factor alpha, transforming growth factor alpha, heparin-binding epidermal growth factor-like growth factor, and Tie-2. Interestingly, an ADAM17-selective inhibitor shortens the duration of VEGF-A-stimulated ERK phosphorylation in human umbilical vein endothelial cells, providing evidence for an ADAM17-dependent crosstalk between the VEGFR2 and ERK signaling. Targeting the sheddases of VEGFR2 or NRP-1 might offer new opportunities to modulate VEGF-A signaling, an already-established target for treatment of pathological neovascularization.
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PMID:VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling. 1881 6

Infantile hemangiomas are characterized by rapid capillary growth during the first year of life followed by involution during early childhood. The natural history of these lesions creates a unique opportunity to study the changes in gene expression that occur in the vessels of these tumors as they proliferate and regress. Here we use laser capture microdissection and genome-wide transcriptional profiling of vessels from proliferating and involuting hemangiomas to identify differentially expressed genes. Relative to normal placental vessels, proliferating hemangiomas were characterized by increased expression of genes involved in endothelial-pericyte interactions, such as angiopoietin-2 (ANGPT2), jagged-1 (JAG1), and notch-4 (NOTCH4), as well as genes involved in neural and vascular patterning, such as neuropilin-2 (NETO2), a plexin domain containing receptor (plexinC1), and an ephrin receptor (EPHB3). Insulin-like growth factor binding protein-3 (IGFBP3) was down-regulated in proliferating hemangiomas. Involuting hemangiomas were characterized by the expression of chronic inflammatory mediators, such as the chemokine, stromal cell-derived factor-1 (SDF-1), and factors that may attenuate the angiogenic response, such as a member of the Down syndrome critical region (DSCR) family. The identification of genes differentially expressed in proliferating and involuting hemangiomas in vivo will contribute to our understanding of this vascular lesion, which remains a leading cause of morbidity in newborn children.
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PMID:Identification of signaling systems in proliferating and involuting phase infantile hemangiomas by genome-wide transcriptional profiling. 1934 69

Neuropilins are membrane proteins that mediate effects on tumor cells directly and indirectly by affecting angiogenesis. Recent findings indicate that neuropilin 1 (NRP1) and the associated tyrosine kinase vascular endothelial growth factor receptor 2 (VEGFR2) play a regulatory role in developmental angiogenesis as well as in tumor angiogenesis. NRP1 and VEGFR2 might play a role in colon carcinogenesis and development of metastases. The significance of NRP1 expression in colon cancer seems to be controversial. Therefore, we aimed to distinguish between different expression patterns of signalling cascades in human colon carcinoma cell lines in order to analyze the role of NRP1 in tumorigenesis. We analyzed the biological significance of NRP1 in respect to VEGFR, EGFR, neuropilin and their ligands by RT-PCR and western blot with functional knock-out of NRP1 in different colon adenocarcinoma cell lines. There was no expression of VEGFR2 in tumor cell lines. There were cells that expressed: i) only NRP1 (HT-29, LS174T), ii) NRP2 (Colo320) or iii) both (SW480, LoVo). Cells without NRP1 expression strongly expressed EGFR but only when NRP2 was co-expressed. Inhibition of NRP1 expression by RNA interference did not alter growth characteristics in soft agar experiments. Furthermore, there were no differences in intracellular signalling pathways (ERK1/2 or AKT) in NRP1 inhibited cells. In ex vivo transfer experiments animals with tumors from siRNA-NRP1 transfected cells showed no significant inhibition of tumor growth compared to siRNA control. In conclusion, our results question the role of NRP1 function in VEGFR2 negative colon adenocarcinoma cells. NRP1 seems to have no detectable effect on proliferation or migration nor does it induce any changes in intracellular signalling pathways without the expression of VEGFR2. According to our data, further studies are needed to analyze the therapeutic relevance of NRP1 inhibition in vivo.
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PMID:No functional and transductional significance of specific neuropilin 1 siRNA inhibition in colon carcinoma cell lines lacking VEGF receptor 2. 1936 Feb 89

Vascular sprouting is a key process-driving development of the vascular system. In this study, we show that neuropilin-2 (Nrp2), a transmembrane receptor for the lymphangiogenic vascular endothelial growth factor C (VEGF-C), plays an important role in lymphatic vessel sprouting. Blocking VEGF-C binding to Nrp2 using antibodies specifically inhibits sprouting of developing lymphatic endothelial tip cells in vivo. In vitro analyses show that Nrp2 modulates lymphatic endothelial tip cell extension and prevents tip cell stalling and retraction during vascular sprout formation. Genetic deletion of Nrp2 reproduces the sprouting defects seen after antibody treatment. To investigate whether this defect depends on Nrp2 interaction with VEGF receptor 2 (VEGFR2) and/or 3, we intercrossed heterozygous mice lacking one allele of these receptors. Double-heterozygous nrp2vegfr2 mice develop normally without detectable lymphatic sprouting defects. In contrast, double-heterozygote nrp2vegfr3 mice show a reduction of lymphatic vessel sprouting and decreased lymph vessel branching in adult organs. Thus, interaction between Nrp2 and VEGFR3 mediates proper lymphatic vessel sprouting in response to VEGF-C.
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PMID:Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. 2006 93


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