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

---

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

Endochondral bone formation is regulated by systemically and locally acting growth factors. A role for vascular endothelial growth factor (VEGF) in this process has recently been proposed, because inactivation of VEGF inhibits endochondral bone formation via inhibition of angiogenesis. Despite the known effect of VEGF as specific endothelial growth factor, its effects on osteoblast differentiation have not been studied. We, therefore, examined the expression of VEGF-A, -B, -C, and -D and their receptors in a model of osteoblast differentiation using the mouse preosteoblast-like cell line KS483. Early in differentiation, KS483 cells express low levels VEGF-A, -B, and -D messenger RNA, whereas during mineralization, KS483 cells express high levels. In addition, expression of the VEGF receptors, VEGFR1, VEGFR2, and VEGF165R/neuropilin, coincided with expression of their ligands, being maximally expressed during mineralization. VEGF-A production during osteoblast differentiation was stimulated by insulin-like growth factor I that enhances osteoblast differentiation and was inhibited by PTH-related peptide that inhibits osteoblast differentiation. Furthermore, continuous treatment of KS483 cells with recombinant human VEGF-A stimulated nodule formation. Although treatment of KS483 cells with soluble FLT1, an agent that blocks binding of VEGF-A and -B to VEGFR1, did not inhibit nodule formation, this observation does not exclude involvement of VEGFR2 in the regulation of osteoblast differentiation. As it is known that VEGF-A, -C, and -D can act through activation of VEGFR2, other isoforms might compensate for VEGF-A loss. The expression pattern of VEGFs and their receptors shown here suggests that VEGFs play an important role in the regulation of bone remodeling by attracting endothelial cells and osteoclasts and by stimulating osteoblast differentiation.
...
PMID:Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. 1080 75

Vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) have been shown to synergistically increase tissue factor (TF) expression in endothelial cells; however, the role of the VEGF receptors (KDR, Flt-1, and neuropilin) in this process is unclear. Here we report that VEGF binding to the KDR receptor is necessary and sufficient for the potentiation of TNF-induced TF expression in human umbilical vein endothelial cells. TF expression was evaluated by Western blot analysis and fluorescence-activated cell sorting. In the absence of TNF-alpha, wild-type VEGF- or KDR receptor-selective variants induced an approximate 7-fold increase in total TF expression. Treatment with TNF alone produced an approximate 110-fold increase in total TF expression, whereas coincubation of TNF-alpha with wild-type VEGF- or KDR-selective variants resulted in an approximate 250-fold increase in TF expression. VEGF lacking the heparin binding domain was also able to potentiate TF expression, indicating that heparin-sulfate proteoglycan or neuropilin binding is not required for TF up-regulation. Neither placental growth factor nor an Flt-1-selective variant was capable of inducing TF expression in the presence or absence of TNF. Inhibition of protein-tyrosine kinase or protein kinase C activity significantly blocked the TNF/VEGF potentiation of TF up-regulation, whereas phorbol 12-myristate 13-acetate, a protein kinase C activator, increased TF expression. These data demonstrate that KDR receptor signaling governs both VEGF-induced TF expression and the potentiation of TNF-induced up-regulation of TF.
...
PMID:Vascular endothelial growth factor KDR receptor signaling potentiates tumor necrosis factor-induced tissue factor expression in endothelial cells. 1105 94

The vascular endothelial growth factor is produced by a large variety of human tumors, including melanoma, in which it appears to play an important role in the process of tumor-induced angiogenesis. Little information is available on the role of placenta growth factor, a member of the vascular endothelial growth factor family of cytokines, in tumor angiogenesis, even though placenta growth factor/vascular endothelial growth factor heterodimers have been recently isolated from tumor cells. To investigate the role of placenta growth factor and vascular endothelial growth factor homodimers and heterodimers in melanoma angiogenesis and growth, 19 human melanoma cell lines derived from primary or metastatic tumors were characterized for the expression of these cytokines and their receptors. Release of placenta growth factor and vascular endothelial growth factor polypeptides into the supernatant of human melanoma cells was demonstrated. Reverse transcriptase polymerase chain reaction analysis showed the presence of mRNAs encoding at least three different vascular endothelial growth factor isoforms (VEGF(121), VEGF(165), and VEGF(189)) and transcripts for two placenta growth factor isoforms (PlGF-1 and PlGF-2) in human melanoma cells. In addition, placenta growth factor expression in human melanoma in vivo was detected by immunohistochemical staining of tumor specimens. Both primary and metastatic melanoma cells were found to express the mRNAs encoding for vascular endothelial growth factor and placenta growth factor receptors (KDR, Flt-1, neuropilin-1, and neuropilin-2), and exposure of melanoma cells to these cytokines resulted in a specific proliferative response, supporting the hypothesis of a role of these angiogenic factors in melanoma growth. J Invest Dermatol 115:1000-1007 2000
...
PMID:Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. 1112 Nov 33

Vascular endothelial growth factor (VEGF) is a potent modulator of vascular remodeling and angiogenesis in the uterus. Recently, neuropilins (Npn), semaphorin receptors associated with neuronal guidance, were demonstrated to bind VEGF isoforms with high affinity, facilitating VEGF(165) binding to the tyrosine kinase receptor VEGFR2. The current studies examined rat uterus neuropilin expression and regulation. Npn-1 and Npn-2 transcripts and 135-kDa proteins were observed in uterine extracts. Both uterine vascular endothelial cells and glandular epithelium expressed Npn-1 immunoreactivity, whereas Npn-2 was restricted to the glandular epithelium. In hormone-replaced ovariectomized animals, progesterone increased uterine 6.5-kb Npn-1 messenger RNA (mRNA) expression approximately 2-fold compared with that in tissues from ovariectomized controls. 17ss-Estradiol alone had no effect, but blunted the progesterone response; by contrast, Npn-2 mRNA expression was decreased by estrogen. VEGFR2 mRNA was coregulated with Npn-1. Consistent with these results, Npn-1 mRNA expression was augmented nearly 7- and 4-fold at metestrus and diestrus, respectively, during periods of high progesterone; Npn-2 mRNA expression was not significantly altered during the estrous cycle. The regulated expression and differential localization of neuropilins in the rat uterus suggest that these receptors may participate in hormonally regulated changes occurring throughout the female reproductive cycle.
...
PMID:Differential expression and regulation of the vascular endothelial growth factor receptors neuropilin-1 and neuropilin-2 in rat uterus. 1115 32

Neuropilin-1 is a VEGF165- and semaphorin receptor expressed by endothelial cells and tumor cells. The specific function of neuropilin-1 is not fully known, but in the developing nervous system neuropilin, as a semaphorin receptor, has been shown to influence neuronal guidance. The expression of neuropilin-1 was studied in low-grade and high-grade astrocytic tumors, the latter characterized by extensive angiogenesis. We examined 20 low-grade astrocytomas (WHO grade II) and 46 glioblastomas (WHO grade IV) immunohistochemically for neuropilin-1, p53 and EGFR. The glioblastomas were according to the p53 and EGFR expression classified as 35 primary--de novo--glioblastomas, 9 secondary glioblastomas, and 2 uncertain cases. Furthermore, the presence of mast cells was evaluated to search for any potential function in angiogenesis. The glioblastomas expressed neuropilin-1 in the endothelial cells of the proliferating vessels and the majority of the glioblastomas had immunoreactive neoplastic astrocytes, with no difference between the glioblastoma subgroups. Six out of twenty of the low-grade astrocytomas were negative in the endothelial cells and 8 out of 20 in the tumor cells for neuropilin-1. Mast cells were observed in the collagen matrix around larger vessels in the leptomeninges, but not adjacent to malignant tumor vessels or as part of the tumor process itself. Increased expression of neuropilin-1 is shown in endothelial cells and in neoplastic astrocytes of glioblastomas. Less neuropilin-1 expression is found in about half of the low-grade astrocytomas in both neoplastic astrocytes and endothelial cells. The results suggest a correlation between neuropilin-1 and vascularity in human astrocytic tumors and a possible role for neuropilin-1 as a receptor for VEGF-induced angiogenesis.
...
PMID:Vascular endothelial growth factor (VEGF) receptor neuropilin-1's distribution in astrocytic tumors. 1523 40

Although much is known about the biology of vascular endothelial growth factor (VEGF) and its cognate receptors (VEGFRs), VEGFR1 and VEGFR2, little is known about the roles of the VEGFRs neuropilin (NP)-1 and NP-2 in the primate endometrium. In this study, we investigated the cellular localization and hormonal regulation of NP-1 and NP-2 mRNA by in situ hybridization in the endometrium of ovariectomized, hormonally cycled rhesus macaques and women during the natural menstrual cycle. NP-1 mRNA was highly expressed in vascular endothelium and in stromal cells, but in these cells, NP-1 expression did not change during the menstrual cycle. However, NP-1 mRNA was also expressed in the luminal epithelium (not the glands), and its expression in these cells was elevated during the mid- to late proliferative phase and completely suppressed during the secretory phase. The increase in NP-1 level in the luminal epithelium was estradiol dependent because such expression was not detectable in the absence of estradiol in ovariectomized, hormone-deprived animals. Moreover, NP-1 expression in the luminal epithelium was highly correlated with the degree of proliferation in these cells. A recent study showed that blockade of VEGF action can inhibit luminal epithelial cell proliferation, but there is no evidence of VEGFR1 and VEGFR2 expression in these cells. Therefore, NP-1 may be the relevant VEGFR that mediates proliferation in this epithelium. NP-2 mRNA, unlike NP-1, was expressed only by the endothelium of veins, and in these cells, its expression was hormonally regulated in the converse manner: it was very low during the proliferative phase and high during the secretory phase. The increased permeability and edema observed during the secretory phase in the primate endometrium may be mediated in part by VEGF-NP-2 interaction. In the human endometrium, the pattern of expression and cellular localization of both NP-1 and NP-2 during the menstrual cycle were essentially identical with that seen in the rhesus macaque endometrium. These are the first data to specify the hormonal regulation and cell-specific expression of NP-1 and NP-2 mRNA in the endometrium of both women and nonhuman primates. The findings extend our understanding of VEGF action in the primate endometrium.
...
PMID:Cellular expression and hormonal regulation of neuropilin-1 and -2 messenger ribonucleic Acid in the human and rhesus macaque endometrium. 1561 13

There is increasing evidence that vascular endothelial growth factor (VEGF) has autocrine as well as paracrine functions in tumour biology. Vascular endothelial growth factor-mediated cell survival signalling occurs via the classical tyrosine kinase receptors Flt-1, KDR/Flk-1 and the more novel neuropilin (NP) receptors, NP-1 and NP-2. A 24-mer peptide, which binds to neuropilin-1, induced apoptosis of murine and human breast carcinoma cells, whereas a peptide directed against KDR had no effect. Both anti-NP1 and anti-KDR peptides induced endothelial cell apoptosis. Confocal microscopy using 5-(6)-carboxyfluorescein-labelled peptides showed that anti-NP1 bound to both tumour and endothelial cells, whereas anti-KDR bound endothelial cells only. This study demonstrates that NP-1 plays an essential role in autocrine antiapoptotic signalling by VEGF in tumour cells and that NP1-blockade induces tumour cell and endothelial cell apoptosis. Specific peptides can therefore be used to target both autocrine (tumour cells) and paracrine (endothelial cells) signalling by VEGF.
...
PMID:A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1-expressing breast tumour cells. 1565 56

The majority of the recognized extracellular signalling molecules are known to participate in paracrine and autocrine functions. The classical model of signalling involves a ligand and its cognate receptor. A unique number of ligands activate two phylogenetically unrelated receptors; some receptors are activated by more than one unrelated polypeptide ligand, and some unrelated receptors share common co-receptors. Such a situation introduces a new dimension of complexity into the processes governed by these signalling mechanisms. These unique 'three-way partnerships' often involve signalling molecules that have key roles in the reproductive system. This review presents the known cases of three-way partnerships and examines their possible significance to the reproductive processes in the ovary and endometrium. Most notably present in the ovary are Wnt, Frizzled, Dickkopf (Dkk), low density lipoprotein receptor-related protein (LRP)5, RYK and Kremen system, and semaphorin, plexin, vascular endothelial growth factor and neuropilin system. In the endometrium one finds potential three-way partnerships in Wnt, Frizzled and RYK system, and ATP, P2X7, P2Y2 system. Three-way partnerships may explain previously enigmatic cases of biphasic effects of a ligand, or may reveal that a ligand thought to be pleiotrophic through the activation of one receptor is actually affecting two unrelated signalling receptors in the same tissue. The potential significance to new pharmacological developments is evident.
...
PMID:Sharing of unrelated receptors and ligands by cognate partners: possible implications for ovarian and endometrial physiology. 1616 28

Inhibition of angiogenesis has become a major target in experimental cancer therapies. Vascular endothelial growth factor (VEGF) and its receptors are essential for breast cancer progression and relevant targets in experimental anti-angiogenesis. VEGF, produced by carcinoma cells, acts in a paracrine fashion on endothelial cells and displays autocrine activity on carcinoma cells. Breast cancer cells express VEGF-A, VEGF-B, VEGF-C and their receptors VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR) and neuropilin (NP-1/NP-2). VEGF-A triggers cellular signalling, an invasive phenotype of certain breast cancer cell lines and influences cell survival. However, such an autocrine VEGF/VEGFR signalling loop remains to be established. We demonstrate production of VEGF-A in cell lines MDA-MB-468, T47d, MCF-7, HBL-100 and in a primary breast cancer culture. Moreover, these cells showed baseline VEGFR-2 tyrosine-phosphorylation that could be enhanced by VEGF-A stimulation. In addition, VEGF-A leads to increased phosphorylation of ERK1/2 and Akt indicating that VEGF-A stimulation plays a crucial role in the regulation of cell growth, apoptosis, survival and differentiation. Moreover, we have established a novel breast cancer cell culture MW1 that expresses high levels of VEGF-A. We demonstrate that VEGFR-2 on the surface of breast cancer cells is functional and is capable of being stimulated by external VEGF-A. VEGF-A production by and VEGFR-2 activation on the surface of breast cancer cells indicates the presence of a distinct autocrine signalling loop that enables breast cancer cells to promote their own growth and survival by phosphorylation and activation of VEGFR-2. Moreover, this autocrine loop represents an attractive therapeutic target.
...
PMID:Autocrine vascular endothelial growth factor signalling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro. 1632 60

Rheumatoid arthritis (RA) synoviocytes are resistant to apoptosis and exhibit a transformed phenotype, which might be caused by chronic exposure to genotoxic stimuli including reactive oxygen species and growth factors. In this study, we investigated the role of vascular endothelial growth factor165 (VEGF165), a potent angiogenic factor, and its receptor in the apoptosis of synoviocytes. We demonstrated here that neuropilin-1, rather than fms-like tyrosine kinase-1 and kinase insert domain-containing receptor, is the major VEGF165 receptor in the fibroblast-like synoviocytes. Neuropilin-1 was highly expressed in the lining layer, infiltrating leukocytes, and endothelial cells of rheumatoid synovium. The production of VEGF165, a ligand for neuropilin, was significantly higher in the RA synoviocytes than in the osteoarthritis synoviocytes. The ligation of recombinant VEGF165 to its receptor prevented the apoptosis of synoviocytes induced by serum starvation or sodium nitroprusside (SNP). VEGF165 rapidly triggered phospho-Akt and phospho-ERK activity and then induced Bcl-2 expression in the rheumatoid synoviocytes. The Akt or ERK inhibitor cancelled the protective effect of VEGF165 on SNP-induced synoviocyte apoptosis. Moreover, VEGF165 blocks SNP-induced Bcl-2 down-regulation as well as SNP-induced Bax translocation from the cytosol to the mitochondria. The down-regulation of the neuropilin-1 transcripts by short interfering RNA caused spontaneous synoviocyte apoptosis, which was associated with both the decrease in Bcl-2 expression and the increase in Bax translocation to mitochondria. Collectively, our data suggest that the interaction of VEGF165 with neuropilin-1 is crucial to the survival of rheumatoid synoviocytes and provide important implications for the abnormal growth of synoviocytes and therapeutic intervention in RA.
...
PMID:Interaction of vascular endothelial growth factor 165 with neuropilin-1 protects rheumatoid synoviocytes from apoptotic death by regulating Bcl-2 expression and Bax translocation. 1701 62


1 2 3 4 Next >>

---