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)

Recently, it has been reported that both thrombin-sensitive protease-activated receptor 1 (PAR-1) and platelet-derived growth factor (PDGF) are present not only in platelets, but also in the CNS, which indicates that they have various physiological functions. In this study, we evaluated whether PAR-1/PDGF in the spinal cord could contribute to the development of a neuropathic pain-like state in mice. Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were significantly suppressed by repeated intrathecal injection of hirudin, which is characterized as a specific and potent thrombin inhibitor. Furthermore, a single intrathecal injection of thrombin produced long-lasting hyperalgesia and allodynia, and these effects were also inhibited by hirudin in normal mice. In nerveligated mice, the increase in the binding of [35S]GTPgammaS to membranes of the spinal cord induced by thrombin and PAR-1-like immunoreactivity (IR) in the spinal cord were each greater than those in sham-operated mice. Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were also suppressed by repeated intrathecal injection of either the PDGF alpha receptor (PDGFRalpha)/Fc chimera protein or the PDGFR-dependent tyrosine kinase inhibitor AG17 [(3,5-di-tert-butyl-4-hydroxybenzylidene)-malononitrile]. Moreover, thermal hyperalgesia and tactile allodynia induced by thrombin in normal mice were virtually eliminated by intrathecal pretreatment with PDGFRalpha/Fc. In immunohistochemical studies, PAR-1-like IR-positive cells in the spinal dorsal horn were mostly colocated on PDGF-like IR-positive neuronal cells. These data provide novel evidence that PAR-1 and PDGF-A-mediated signaling pathway within spinal cord neurons may be directly implicated in neuropathic pain after nerve injury in mice.
...
PMID:Protease-activated receptor-1 and platelet-derived growth factor in spinal cord neurons are implicated in neuropathic pain after nerve injury. 1625 48

In this study we have investigated the effect of human neutrophil on agonist-induced platelet aggregation by using the laser-light scattering method that can detect a two-phase process, formation of small aggregates followed by large aggregate formation. When nonstimulated neutrophils were added to agonist-stimulated platelet-rich plasma (PRP), the large platelet aggregates were decreased and the small ones were increased by using either collagen, thrombin or ADP as agonist. Scanning-electron microscopic observation showed marked adhesion of neutrophil to aggregated platelets. The supernatant from neutrophils cell lysate (neutrophil supernatant) showed inhibitory effect similar to that with intact neutrophils, suggesting that the inhibitory effect by neutrophils was due to soluble component(s) including proteases released from neutrophils adhered to activated platelets. We have examined the effect of inhibition of a major released protease, elastase. The addition of its potent inhibitor elafin to intact neutrophils or the neutrophil supernatant changed their antiaggregating activity. The treatment of platelets with genistein, an inhibitor of protein tyrosine kinase, decreased agonist-induced large aggregates and increased small ones, suggesting that certain protein tyrosine kinase would be involved in the transition from small to large platelet aggregates. It was also shown that the tyrosine phosphorylation induced by agonist stimulation of several high molecular-weight proteins of platelets was inhibited by coincubation with neutrophils, concurrent with increases in smaller phosphorylated proteins. In washed platelets, coincubation with neutrophils resulted in reduced formation of large aggregates when stimulated with collagen or thrombin and repressed agonist-induced activation of tyrosine protein kinases (Syk, Lyn, Src, and Pyk2), but not thrombin-induced ERK and p38 MAP kinase. These results suggest that the cleavage of platelet membrane glycoproteins at least in part by elastase which was released from neutrophils, is involved in the inhibition of the transition from small to large platelet aggregates.
...
PMID:Effect of neutrophil adhesion on the size of aggregates formed by agonist-activated platelets. 1628 15

The flow-responsive transcription factor KLF2 is acquiring a leading role in the regulation of endothelial cell gene expression. A genome-wide microarray expression profiling is described employing lentivirus-mediated, 7-day overexpression of human KLF2 at levels observed under prolonged flow. KLF2 is not involved in lineage typing, as 42 endothelial-specific markers were unaffected. Rather, KLF2 generates a gene transcription profile (> 1000 genes) affecting key functional pathways such as cell migration, vasomotor function, inflammation, and hemostasis and induces a morphology change typical for shear exposure including stress fiber formation. Protein levels for thrombomodulin, endothelial nitric oxide synthase, and plasminogen activator inhibitor type-1 are altered to atheroprotective levels, even in the presence of the inflammatory cytokine TNF-alpha. KLF2 attenuates cell migration by affecting multiple genes including VEGFR2 and the potent antimigratory SEMA3F. The distribution of Weibel-Palade bodies in cultured cell populations is normalized at the single-cell level without interfering with their regulated, RalA-dependent release. In contrast, thrombin-induced release of Weibel-Palade bodies is significantly attenuated, consistent with the proposed role of VWF release at low-shear stress regions of the vasculature in atherosclerosis. These results establish that KLF2 acts as a central transcriptional switch point between the quiescent and activated states of the adult endothelial cell.
...
PMID:KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. 1645 54

Sigma receptors have no known homology with other receptor systems, have no known natural ligands, but appear to play a critical role in a large diversity of cell functions. In the absence of a conventional pharmacology, siRNA technology provides a direct means of elucidating the major cell signaling pathways influenced by this receptor system. The non-transformed human lens cell line FHL124 was found to express the sigma-1 receptor (Sig-1R) and was employed for these studies. 72 h of transfection with either of the two siRNA directed against the sigma-1 receptor reduced messenger RNA and protein levels by over 70 and 60% respectively. Subsequent incubation for 96 h in culture medium (EMEM) supplemented with 5% serum gave a partial recovery of message, but there was no significant increase in protein. LDH leakage assays showed that significant cell death occurred during this time with an increased expression of caspase-3. Thrombin (10 nM) drives the growth of lens cells with a concomitant increase in ERK and Akt phosphorylation. These increases were inhibited in the cells where knockdown had occurred but not in cells exposed to scrambled siRNA. This study establishes a central role for Sig-1R in cell survival and death.
...
PMID:Silencing of sigma-1 receptor induces cell death in human lens cells. 1647 3

Staphylococcal enterotoxin (SE) B, a heat-stable toxin secreted by Staphylococcus aureus, has been implicated in the pathogenesis and exacerbation of several critical illnesses. It has been hypothesized that enterotoxins may interact with blood products such as platelets, in addition to T-lymphocytes and renal proximal tubule cells. The aim of this present study was to elucidate whether SEB directly alters human platelet function. Human platelet rich plasma (PRP) was pre-incubated with SEA, SEB, SEC or TSST-1, (at various concentrations and incubation times). After incubation, PRP was exposed to thrombin and aggregation was assessed. Incubation with all toxins tested resulted in decreased aggregation, specifically; exposure to 10mu g/ml of SEB for 30 min caused a 20% decrease and a 49% decrease at 90 min. A similar reduction in aggregation was seen in samples incubated with phorbol myristate acetate, a known stimulator of protein kinase C (PKC). Further, platelets exposed to SEB exhibited an increased plasma membrane PKC activity. Sphingosine, an inhibitor of PKC proved to block the SEB-induced reduction in aggregation. SEB effects on platelet metabolism were investigated using high performance liquid chromatography showing up to a 2-fold increase of active metabolites lipoxin A4 and 12-HETE, as compared to control. These data indicate that SEB is able to induce platelet dysfunction, and these effects may be mediated through activation of PKC.
...
PMID:Staphylococcal enterotoxin B initiates protein kinase C translocation and eicosanoid metabolism while inhibiting thrombin-induced aggregation in human platelets. 1655 Feb 98

The mechanism of thrombin-induced angiogenesis is poorly understood. Using a gene chip array to investigate the pro-malignant phenotype of thrombin-stimulated cells, we observed that thrombin markedly up-regulates growth-regulated oncogene-alpha (GRO-alpha) in several tumor cell lines as well as endothelial cells by mRNA and protein analysis. Thrombin enhanced the secretion of GRO-alpha from tumor cells 25- to 64-fold. GRO-alpha is a CXC chemokine with tumor-associated angiogenic as well as oncogenic activation following ligation of its CXCR2 receptor. GRO-alpha enhanced angiogenesis in the chick chorioallantoic membrane assay 2.2-fold, providing direct evidence for GRO-alpha as an angiogenic growth factor. Anti-GRO-alpha antibody completely inhibited the 2.7-fold thrombin-induced up-regulation of angiogenesis, as well as the 1.5-fold thrombin-induced up-regulation of both endothelial cell cord formation in Matrigel and growth in vitro. Thrombin as well as its PAR-1 receptor activation peptide [thrombin receptor activation peptide (TRAP)] as well as GRO-alpha all markedly increased vascular regulatory proteins and growth factors: matrix metalloproteinase (MMP)-1, MMP-2, vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), CD31, and receptors KDR and CXCR2 in human umbilical vein endothelial cells. All of the thrombin/TRAP gene up-regulations were completely inhibited by anti-GRO-alpha antibody and unaffected by irrelevant antibody. Similar inhibition of gene up-regulation as well as thrombin-induced chemotaxis was noted with small interfering RNA (shRNA) GRO-alpha KD 4T1 breast tumor and B16F10 melanoma cells. In vivo tumor growth studies in wild-type mice with shRNA GRO-alpha KD cells revealed 2- to 4-fold impaired tumor growth, metastasis, and angiogenesis, which was not affected by endogenous thrombin. Thus, thrombin-induced angiogenesis requires the up-regulation of GRO-alpha. Thrombin up-regulation of GRO-alpha in tumor cells as well as endothelial cells contributes to tumor angiogenesis.
...
PMID:Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. 1661 33

Progression of human malignancies is accompanied by vascular events, such as formation and remodeling of blood vessels and systemic coagulopathy. Though long appreciated as comorbidity of cancer (Trousseau syndrome), vascular involvement is increasingly recognized as a central pathogenetic mechanism of tumor growth, invasion and metastasis. The major outstanding question in relation to this role has been, whether vascular perturbations are simply a reaction to the conditions of the tumor microenvironment, or are linked to the known genetic lesions causal for the onset and progression of malignancy. In this regard, we have previously hypothesized, and recently demonstrated experimentally that deregulation of certain hemostatic mechanisms, namely upregulation of tissue factor (TF) and possibly other changes (e.g. expression of thrombin receptor - PAR-1) are controlled by cancer-associated oncogenic events, such as activation of K-ras, epidermal growth factor receptor (EGFR), or inactivation of the p53 tumor suppressor gene in various human cancer cells. It appears that these respective transforming alterations exert their impact on both, cell-associated and soluble/circulating (microvesicle- associated) TF, i.e. may cause a systemic hypercoagulable state. Other genes, which more recently emerged as regulators of cancer coagulopathy include: PML-RARalpha, PTEN, and MET. While the spectrum of procoagulant targets of these genes may vary somewhat it includes: TF, PAI-1, COX-2 and possibly other hemostatic proteins. It is noteworthy that these prothrombotic changes may impact the malignant process directly (e.g. stimulate angiogenesis, tumor growth or metastasis) as a consequence of both coagulation-dependent and -independent effects. The latter are mostly related to cellular signaling events and changes in gene expression which are now known to be induced by the TF/FVIIa/Xa complex, thrombin and PARs, expressed on the surface of cancer cells, as well as tumor-associated endothelium. Interestingly, certain anticoagulants possess antimetastatic and anticancer properties (e.g. LMWH), an observation that further suggests that hypercoagulability may act as an effector mechanism of genetically driven tumor progression. Conversely, we suggest that oncogene-directed (targeted) anticancer agents could, at least in some cases, ameliorate not only cellular transformation itself, but also some of the chronic components of the cancer-related coagulopathy, something that may be relevant to therapeutic efficacy of these drugs. We also postulate that since TF is the oncogene target, circulating TF (microparticles) could serve as surrogate marker of the biological activity oncogene-directed agents exert in vivo. Thus, both genetic and epigenetic factors appear to conspire to activate various components of the hemostatic system in cancer patients, both locally and systemically. These activities act as mediators of cancer coagulopathy, angiogenesis, metastasis and other events involved in disease progression and should be recognized in designing better anticancer therapies.
...
PMID:Genetic determinants of cancer coagulopathy, angiogenesis and disease progression. 1663 63

Thrombin activates protease-activated receptor-1 (PAR-1) and engages signaling pathways that influence the growth and survival of cardiomyocytes as well as extracellular matrix remodeling by cardiac fibroblasts. This study examines the role of Shc proteins in PAR-1-dependent signaling pathways that influence ventricular remodeling. We show that thrombin increases p46Shc/p52Shc phosphorylation at Tyr(239)/Tyr(240) and Tyr(317) (and p66Shc-Ser(36) phosphorylation) via a pertussis toxin-insensitive epidermal growth factor receptor (EGFR) transactivation pathway in cardiac fibroblasts; p66Shc-Ser(36) phosphorylation is via a MEK-dependent mechanism. In contrast, cardiac fibroblasts express beta(2)-adrenergic receptors that activate ERK through a pertussis toxin-sensitive EGFR transactivation pathway that does not involve Shc isoforms or lead to p66Shc-Ser(36) phosphorylation. In cardiomyocytes, thrombin triggers MEK-dependent p66Shc-Ser(36) phosphorylation, but this is not via EGFR transactivation (or associated with Shc-Tyr(239)/Tyr(240) and/or Tyr(317) phosphorylation). Importantly, p66Shc protein expression is detected in neonatal, but not adult, cardiomyocytes; p66Shc expression is induced (via a mechanism that requires protein kinase C and MEK activity) by Pasteurella multocida toxin, a Galpha(q) agonist that promotes cardiomyocyte hypertrophy. These results identify novel regulation of individual Shc isoforms in receptor-dependent pathways leading to cardiac hypertrophy and the transition to heart failure. The observations that p66Shc expression is induced by a Galpha(q) agonist and that PAR-1 activation leads to p66Shc-Ser(36) phosphorylation identifies p66Shc as a novel candidate hypertrophy-induced mediator of cardiomyocyte apoptosis and heart failure.
...
PMID:Distinct signaling functions for Shc isoforms in the heart. 1669 71

We have recently demonstrated that thrombin-activated FXIII (FXIIIA-subunit), a plasma transglutaminase, activates VEGFR-2 by crosslinking it with the alpha(v)beta(3) integrin on the surface of endothelial cells (EC), thereby stimulating angiogenesis. Tissue transglutaminase (tTG), which is functionally and structurally related to FXIIIA, is expressed by numerous cell types, among them EC. However, its role in EC function has not been fully characterized. In the present study, we investigated the potential involvement of tTG in angiogenesis. Using co-immunoprecipitation and immunofluorescent staining experiments, we observed that tTG forms a complex with VEGFR-2 on the cell surface and within the cytoplasm of EC. Stimulation of EC with VEGF resulted in translocation of the tTG-VEGFR-2 complex from the cytoplasm to the nucleus. In VEGF-treated cells, tTG-VEGFR-2 interaction resulted in incorporation of VEGFR-2 into high molecular weight crosslinked complex (es), as revealed by an antibody against gamma-glutamyl-epsilon-lysine isopeptide bond. tTG -VEGFR-2 association was inhibited by a specific VEGFR-2 protein tyrosine kinase inhibitor (PTKI ), as well as by cystamine, inhibitor of the transglutaminase activity of tTG, but not by bacitracin which inhibits the protein-disulfide isomerase (PDI) activity of tTG. Furthermore, cystamine completely abolished the VEGF-induced nuclear translocation of the tTG-VEGFR-2 complex. Blockade of the crosslinking activity of tTG by cystamine enhanced VEGF-induced migration of EC in Boyden chamber by 31% (P < 0.02), and prolonged VEGF-induced signaling response, as demonstrated by sustained activation of the MAP kinase ERK. Taken together, our findings suggest that endothelial cell tTG might be involved in modulation of the cellular response to VEGF by forming an intracellular complex with VEGFR-2, and mediating its translocation into the nucleus upon VEGF stimulation.
...
PMID:Complex formation between tissue transglutaminase II (tTG) and vascular endothelial growth factor receptor 2 (VEGFR-2): proposed mechanism for modulation of endothelial cell response to VEGF. 1691 40

p38 MAP kinase in human platelets is activated by platelet agonists including thrombin, thromboxane A2 (TxA2), ADP, and others. However, both upstream mechanisms of p38 MAP kinase activation, and their downstream sequelae, are presently controversial and essentially unclear. Certain studies report sequential activation of cGMP-dependent protein kinase (PKG) and p38/ERK pathways by platelet agonists, leading to integrin activation and secretion, whereas others establish an essential role of Src/ERK-mediated TxA2 generation for fibrinogen receptor activation in human platelets. Here, we show that ADP secreted from platelet-dense granules, and subsequent activation of P2Y12 receptors, as well as TxA2 release are important upstream mediators of p38 MAP kinase activation by thrombin. However, p38 MAP kinase activation did not significantly contribute to calcium mobilization, P-selectin expression, alphaIIbbeta3 integrin activation, and aggregation of human platelets in response to thrombin. Finally, PKG activation did not stimulate, but rather inhibited, p38 MAP kinase in human platelets.
...
PMID:Thrombin stimulation of p38 MAP kinase in human platelets is mediated by ADP and thromboxane A2 and inhibited by cGMP/cGMP-dependent protein kinase. 1699 May 90


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---