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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The factor VII activating protease (FSAP) is a serine-protease present in human plasma that serves to activate single-chain plasminogen activators, as well as coagulation factor VII. FSAP was localized within atherosclerotic lesions, and a genetic polymorphism in FSAP is associated with carotid stenosis. Hence, this study was conducted to gain broader insights into the cellular effects of FSAP on vascular smooth muscle cells (VSMC). DNA synthesis and cell proliferation assays revealed an inhibitory action of FSAP on platelet-derived growth factor BB (PDGF-BB)-mediated proliferation of VSMC. FSAP also inhibited PDGF-BB-induced migration of VSMC. These cellular effects of FSAP could be neutralized by an anti-FSAP mAb as well as by protease inhibitors such as aprotinin or a chloromethylketone inhibitor. Moreover, unfractionated heparin promoted the antiproliferative effect of FSAP on VSMC and was essential for the inhibition of VSMC migration. FSAP inhibited PDGF-BB binding to human VSMC and concomitantly blocked PDGF-BB-dependent phosphorylation of mitogen activated protein kinase p42/p44 and tyrosine phosphorylation of other proteins. These results unravel a new function of FSAP as an inhibitor of the proatherogenic phenotype of vascular smooth muscle.
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PMID:Factor VII-activating protease (FSAP) inhibits growth factor-mediated cell proliferation and migration of vascular smooth muscle cells. 1497 86

The presence and the different functional aspects of cytokine-related molecules in invertebrates are described. Cytokine-like factors affect immune functions, such as cell motility, chemotaxis, phagocytosis and cytotoxicity. In particular, cell migration shows a species-specific effect for IL-1alpha and TNF-alpha and a dose-correlated effect for IL-8, PDGF-AB and TGF-beta1. Apart from some exceptions, the phagocytic effect increases significantly at all the concentrations tested and with all the species used. PDGF-AB, TGF-beta1 and IL-8 provoke conformational changes in mollusk immunocytes, involving the signaling transduction pathways of phosphatidylinositol and cAMP. PDGF-AB and TGF-beta1 partially inhibit the induced programmed cell death in an insect cell line, and the survival effect is mediated by the activation of phosphatidylinositol 3-kinase, PKA and PKC. The exogenous administration of these growth factors in an invertebrate wound repair model showed that they are able to control the wound environment and promote the repair process by accelerating the coordinated activities involved. Moreover, IL-1alpha, IL-2 and TNF-alpha are able to induce nitric oxide synthase. PDGF-AB and TGF-beta1 provoke an increase in neutral endopeptidase-24.11 (NEP)-like activity in membrane preparations from mollusk immunocytes, while NEP deactivates the PDGF-AB- and TGF-beta1-induced cell shape changes. Cytokines are also involved in invertebrate stress response in a manner extremely similar to that in vertebrates. Several studies suggest the existence on the mollusk immunocyte membrane of an ancestral receptor capable of binding both IL-2 and CRH. Furthermore, the competition found between CRH and a large number of cytokines supports the idea that invertebrate cytokine receptors show a certain degree of promiscuity. The multiple functions of cytokines detected in invertebrates underline another characteristic of mammalian cytokines, i.e. their great pleiotropicity. Altogether, the studies on the function of the invertebrate humoral factors show a close overlapping with those found in vertebrates, and the hypothesized missing correlation between invertebrate and vertebrate cytokine genes that is emerging from the limited molecular biology data present in literature might represent a very peculiar strategy followed by Nature in the evolution of cytokines.
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PMID:Invertebrate humoral factors: cytokines as mediators of cell survival. 1497 62

MC (mesangial cell) proliferation is closely linked to the progression of glomerular disease. It has been reported that cAMP effectors suppress MC proliferation, inhibiting activation of MAPK (mitogen-activated protein kinase). In fibroblasts, activation of MAPK induces the expression of type D cyclin, whereas, in MCs, this induction has not been shown. In the present study, we explored the effects of cAMP on MAPK and expression of cell-cycle-regulated proteins. PDGF (platelet-derived growth factor) stimulated MAPK activity, up-regulated protein levels of cyclin D1, CDK2 (cyclin-dependent kinase 2) and PCNA (proliferating cell nuclear antigen), decreased the protein level of p27 and increased DNA synthesis. Fsk (forskolin) or PD98059 suppressed PDGF-induced DNA synthesis. Both agents inhibited PDGF-stimulated mRNA and protein expression of cyclin D1 and CDK2. Fsk or PD98059 also inhibited protein expression of PCNA and blocked a decrease in p27 protein. Fsk induced the phosphorylation of Raf-1 at Ser259, which was inhibited by KT5720. These data suggest that cAMP inhibits MC proliferation through inhibition of MAPK activity, and this mechanism partly involves alteration in the levels of cell-cycle-regulated proteins.
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PMID:Role of cyclins in cAMP inhibition of glomerular mesangial cell proliferation. 1499 82

Recent studies have demonstrated that H(2)O(2) acts as a second messenger of mitogenic signaling and that catalase is under the regulation of PKA and PKC signaling. Here we examined whether catalase binds any mitogenic signaling molecules. Our results indicated that serum stimulation of HeLa, Caco-2, and LiSa-2 cells, but not BJ-1 and primary human bronchial epithelial cells, resulted in catalase binding to Grb2. Whereas serum deprivation, butyrate, and herbimycin-A negatively regulated the binding, an extended culture of confluent Caco-2 cells resulted in binding of an additional but as yet unidentified molecule to the Grb2-catalase complex. Expression of active catalase nearly 15-fold over control level in Tet-off HeLa cells substantially increased binding to Grb2, and this was sensitive to 3-aminotriazole, a specific catalase inhibitor. Furthermore, fibrinogen, fibronectin, and laminin, but not collagen types I to V, hyaluronic acid, elastin, insulin, EGF, IGF-I, PDGF, or NGF, resulted in binding similar to that of serum. A mutation of tyrosine to phenylalanine at 447 abolished the binding capability of catalase to Grb2 in vitro. These results support the view that catalase (447)Tyr-Val-Asn-Val binds Grb2 upon phosphorylation in tumor cells when stimulated with serum or ligands for integrin receptors. This is the first report demonstrating that catalase binds a SH2 domain of the molecule and participates in integrin signaling.
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PMID:Catalase binds Grb2 in tumor cells when stimulated with serum or ligands for integrin receptors. 1518 56

Diabetes mellitus is a major risk factor in the development of atherosclerosis and cardiovascular disease conditions, involving intimal injury and enhanced vascular smooth muscle cell (VSMC) migration. We report a mechanistic basis for divergences between insulin's inhibitory effects on migration of aortic VSMC from control Wistar Kyoto (WKY) rats versus Goto-Kakizaki (GK) diabetic rats. In normal WKY VSMC, insulin increased MAPK phosphatase-1 (MKP-1) expression as well as MKP-1 phosphorylation, which stabilizes it, and inhibited PDGF-mediated MAPK phosphorylation and cell migration. In contrast, basal migration was elevated in GK diabetic VSMCs, and all of insulin's effects on MKP-1 expression and phosphorylation, MAPK phosphorylation, and PDGF-stimulated migration were markedly inhibited. The critical importance of MKP-1 in insulin inhibition of VSMC migration was evident from several observations. MKP-1 small interfering RNA inhibited MKP-1 expression and abolished insulin inhibition of PDGF-induced VSMC migration. Conversely, adenoviral expression of MKP-1 decreased MAPK phosphorylation and basal migration rate and restored insulin's ability to inhibit PDGF-directed migration in GK diabetic VSMCs. Also, the proteasomal inhibitors lactacystin and MG132 partially restored MKP-1 protein levels in GK diabetic VSMCs and inhibited their migration. Furthermore, GK diabetic aortic VSMCs had reduced cGMP-dependent protein kinase Ialpha (cGK Ialpha) levels as well as insulin-dependent, but not sodium nitroprusside-dependent, stimulation of cGMP. Adenoviral expression of cGK Ialpha enhanced MKP-1 inhibition of MAPK phosphorylation and VSMC migration. We conclude that enhanced VSMC migration in GK diabetic rats is due at least in part to a failure of insulin-stimulated cGMP/cGK Ialpha signaling, MKP-1 expression, and stabilization and thus MAPK inactivation.
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PMID:MKP-1 expression and stabilization and cGK Ialpha prevent diabetes- associated abnormalities in VSMC migration. 1535 57

Proliferation of vascular smooth muscle cells (VSMCs) is induced by various mitogens through activation of extracellular signal-regulated protein kinase (ERK) pathway. We recently reported that peroxisome proliferator-activated receptor (PPAR)gamma activators such as 15-deoxy-Delta12,14-prostaglandin J2 (15-d-PGJ2) and thiazolidinediones (TZDs) activated MEK/ERK pathway through phosphatidylinositol 3-kinase (PI3-K) and induced proliferation of VSMCs. However, the precise mechanisms of PPARgamma activators-induced activation of PI3-K/ERK pathway have not been determined. We examined whether transactivation of growth factor receptor is involved in this process. Stimulation of VSMCs with 15-d-PGJ2 or TZDs for 15 min induced phosphorylation of ERK1/2 and Akt. 15-d-PGJ2- or TZDs-induced phosphorylation of ERK1/2 and Akt was inhibited by AG1478, an inhibitor of epidermal growth factor receptor (EGF-R) as well as AG1295, an inhibitor of platelet derived growth factor receptor (PDGF-R). 15-d-PGJ2-induced phosphorylation of both EGF-R and PDGF-R. GM6001, a matrix metalloproteinase inhibitor, and PP2, a Src family protein kinase inhibitor, suppressed 15-d-PGJ2- and TZDs-induced phosphorylation of EGF-R and PDGFbeta-R as well as activation of ERK1/2 and Akt. PDGFbeta-R was co-immunoprecipitated with EGF-R, regardless of the presence or absence of 15-d-PGJ2. These data suggest that 15-d-PGJ2 and TZDs activate PI3-K/ERK pathway through Src family kinase- and matrix metalloproteinase-dependent transactivation of EGF-R and PDGF-R. Both receptors seemed to associate constitutively. This novel signaling mechanisms may contribute to diverse biological functions of PPARgamma activators.
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PMID:15-Deoxy-Delta12,14-prostaglandin J2 and thiazolidinediones transactivate epidermal growth factor and platelet-derived growth factor receptors in vascular smooth muscle cells. 1536 66

cAMP has been found to play a role in mediating the negative regulation of cell motility, although its underlying molecular mechanism remains poorly understood. By using CHO (Chinese-hamster ovary) cells that express the EP2 subtype of PGE2 (prostaglandin E2) receptors, we provide evidence that an increase in cellular cAMP content leads to inhibition of cellular Rac activity, which serves as a mechanism for this negative regulation. In CHO cells expressing EP2, but not in vector control cells, PGE2 dose-dependently inhibited chemotaxis towards IGF-I (insulin-like growth factor-I), which is a Rac-dependent process, with the maximal 75% inhibition observed at 10(-8) M PGE2. EP2 stimulation failed to inhibit tyrosine phosphorylation either of IGF-I receptor or IRS-1 (insulin receptor substrate-1), or activation of phosphoinositide 3-kinase or Akt in response to IGF-I, but potently and dose-dependently inhibited IGF-I-induced activation of cellular Rac activity and membrane ruffling. However, PGE2 failed to inhibit Val12-Rac-induced membrane ruffling. Similar to the case of CHO cells, PGE2 inhibited PDGF (platelet-derived growth factor)-induced Rac activation and chemotaxis in vascular smooth muscle cells endogenously expressing EP2. The inhibitory effects of PGE2 on IGF-I-induced chemotaxis, membrane ruffling and Rac activation were faithfully reproduced by a low concentration of forskolin, which induced a comparable extent of cAMP elevation as with 10(-8) M PGE2, and were potentiated by isobutylmethylxanthine. The protein kinase A inhibitor Rp isomer of adenosine 3',5'-cyclic monophosphorothioate reduced PGE2 inhibition of Rac activation and chemotaxis. These results indicate that EP2 mediates Rac inhibition through a mechanism involving cAMP and protein kinase A, thereby inhibiting membrane ruffling and chemotaxis.
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PMID:Inhibition of Rac activation as a mechanism for negative regulation of actin cytoskeletal reorganization and cell motility by cAMP. 1537 80

1 Sphingosine-1-phosphate (S1P) is considered a potent mitogen for mesangial cells and activates the classical mitogen-activated protein kinase (MAPK) cascade via S1P receptors. In this study, we show that S1P signalling is rapidly desensitized upon S1P receptor activation. A complete loss of S1P sensitivity occurs after 10 min of S1P pretreatment and remains for at least 8 h. A similar desensitization is also seen with the S1P mimetic FTY720-phosphate, but not with the nonphosphorylated FTY720, nor with sphingosine or ceramide. 2 Prestimulating the cells with extracellular ATP or UTP, which bind to and activate P2Y receptors on mesangial cells, a similar rapid desensitization of the S1P receptor occurs, suggesting a heterologous desensitization of S1P receptors by P2Y receptor activation. Furthermore, adenosine binding to P1 receptors triggers a similar desensitization. In contrast, two other growth factors, PDGF-BB and TGFbeta2, have no significant effect on S1P-induced MAPK activation. 3 S1P also triggers increased inositol trisphosphate (IP3) formation, which is completely abolished by S1P pretreatment but only partially by ATP pretreatment, suggesting that IP3 formation and MAPK activation stimulated by S1P involve different receptor subtypes. 4 Increasing intracellular cAMP levels by forskolin pretreatment has a similar effect on desensitization as adenosine. Moreover, a selective A3 adenosine receptor agonist, which couples to phospholipase C and increases IP3 formation, exerted a similar effect. 5 Pretreatment of cells with various protein kinase C (PKC) inhibitors prior to ATP prestimulation and subsequent S1P stimulation leads to a differential reversal of the ATP effect. Whereas the broad-spectrum protein kinase inhibitor staurosporine potently reverses the effect, the PKC-alpha inhibitor CGP41251, the PKC-delta inhibitor rottlerin and calphostin C show only a partial reversal at maximal concentrations. 6 Suramin, which is reported as a selective S1P3 receptor antagonist compared to the other S1P receptor subtypes, has no effect on the S1P-induced MAPK activation, thus excluding the involvement of S1P3 in this response. 7 In summary, these data document a rapid homologous and also heterologous desensitization of S1P signalling in mesangial cells, which is mechanistically triggered by PKC activation and eventually another staurosporine-sensitive protein kinase, as well as by increased cAMP formation.
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PMID:Heterologous desensitization of the sphingosine-1-phosphate receptors by purinoceptor activation in renal mesangial cells. 1546 46

Labedipinedilol-A is a novel 1, 4-dihydropyridine type calcium antagonist with alpha-receptor blocking activity. This study investigates the effects of labedipinedilol-A on mitogen-induced proliferation of rat vascular smooth muscle cells (VSMCs). Labedipinedilol-A's inhibition on cell proliferation was measured by the tetrazolium salt (XTT) test. Labedipinedilol-A dose-dependently inhibited mitogen-induced DNA synthesis, determined by the incorporation of 5-bromo-2'-deoxyuridine (BrdU). Labedipinedilol-A was also found capable of inhibiting the migration of VSMCs induced by PDGF-BB with an IC50 value of 5.6 microM. In accordance with these findings, labedipinedilol-A revealed blocking of the FBS-inducible progression through G0/G1 to S phase of the cell cycle in synchronized cells. Labedipinedilol-A appeared to cause inhibition of mitogens-induced PKC translocation, suggesting the probable involvement of protein kinase C (PKC) in this cellular response. Labedipinedilol-A reduced both intracellular Ca and the phosphorylation of extracellular signal-regulated protein kinase 1/2 in PDGF-BB-stimulated VSMCs. It also suppressed the levels of proliferative cell nuclear antigen (PCNA) in VSMCs both time- and dose-dependently. These results indicate that labedipinedilol-A may inhibit cell proliferation by attenuating activation of the ERK 1/2 pathway, which is regulated by PKC and Ca, suggesting that it may have great potential in the prevention of progressive atherosclerosis.
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PMID:Inhibition of mitogen-mediated proliferation of rat vascular smooth muscle cells by labedipinedilol-A through PKC and ERK 1/2 pathway. 1550 90

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and by obstructive changes of the pulmonary vasculature including smooth muscle cell proliferation which leads to medial hypertrophy and subsequent luminal narrowing. Sildenafil, an orally active inhibitor of cGMP phosphodiesterase-type-5, exerts pulmonary vasodilator activity in PAH patients. We evaluated the effects of sildenafil on growth of cultured human pulmonary artery smooth muscle cells (PASMC). The results indicate that sildenafil reduced DNA synthesis stimulated by PDGF and dose dependently inhibited PASMC proliferation. These effects were paralleled by a progressive increase in cGMP content, followed by an accumulation of cAMP. The treatment with 8-bromo-cGMP or dibutyryl-cAMP mimicked all the effects of sildenafil. On the other hand, treatment of PASMC with inhibitors of cGMP-dependent protein kinase (PKG) or cAMP-dependent protein kinase (PKA) reversed the antiproliferative effect of sildenafil. In addition, sildenafil inhibited the phosphorylation of ERK, a converging point for several pathways leading to cell proliferation. This effect was partially reduced by PKG inhibition and completely abolished by PKA inhibition.We conclude that sildenafil exerts an antiproliferative effect on human PASMC that is mediated by an interaction between the cGMP-PKG and the cAMP-PKA activated pathways, leading to inhibition of PDGF-mediated activation of the ERK.
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PMID:Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. 1573 22


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