Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently demonstrated that, in rat aortic smooth muscle cells, alpha-thrombin stimulated Stat3/SIF-A (signal transducers and activators of transcription 3/sis-inducing factor-A) activity [G. J. Bhat et al. (1997) Hypertension 29(Pt. 2), 356-360]. In the present study, we observed that exposure of CCL39 cells (a Chinese hamster lung fibroblast cell line) to alpha-thrombin resulted in a time-dependent decrease in basal SIF-A activity. We hypothesized that the decrease in basal SIF-A was due to the initiation of an inhibitory pathway, following alpha-thrombin exposure. To test this hypothesis, we determined if alpha-thrombin would inhibit Stat3 and SIF-A activation by interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF). In support of this hypothesis, alpha-thrombin inhibited the Stat3/SIF-A response induced by all the above cytokines. The inhibition by alpha-thrombin was concentration dependent, was sensitive to hirudin, and was mimicked by the thrombin receptor agonist peptide. The inhibition did not require the activation of phorbol 12-myristate 13-acetate-sensitive isoforms of protein kinase C and was reversed by pretreatment with the mitogen-activated protein kinase kinase 1 (MAPKK1 or MEK1) inhibitor PD98059. Inhibitory cross talk between alpha-thrombin and IL-6 was also observed in MRC-5 cells, a fibroblast cell line derived from human lung tissue. Thus, we identify a novel alpha-thrombin inhibitory pathway which, acting through a MAPKK1-dependent mechanism, blocks IL-6-, LIF-, and CNTF-induced Stat3/SIF-A activation. This inhibitory cross talk may provide an important regulatory function to modulate gene transcription by these cytokines, during immune and inflammatory responses.
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PMID:alpha-Thrombin inhibits signal transducers and activators of transcription 3 signaling by interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor in CCL39 cells. 947 6

Proliferation of airway smooth muscle results from persistent inflammatory cytokine and growth factor stimulation and is a critical component of airway luminal narrowing in chronic asthma. Using primary cultures of bovine tracheal smooth muscle (BTSM) cells to examine the signaling basis of cell proliferation, platelet-derived growth factor (PDGF)-BB and thrombin (which act through distinct receptor types) were found to induce DNA synthesis in BTSM cells. Mitogen-induced DNA synthesis could be completely inhibited by LY294002, a selective phosphoinositide 3-kinase (PtdIns 3-kinase) inhibitor. Exposure of BTSM cells to PDGF-BB or thrombin resulted in rapid activation of PtdIns 3-kinase and accumulation of phosphoinositide-3,4,5-trisphosphate. Protein kinase B, a novel signaling protein kinase, was identified in BTSM cells and was activated by PDGF-BB and thrombin in a PtdIns 3-kinase-dependent manner; this may underlie mitogen-stimulated activation of p70(s6k). PD98059, a mitogen-activated protein kinase kinase 1 inhibitor, also partially inhibited PDGF-BB- and thrombin-stimulated DNA synthesis, indicating a modulatory role for mitogen-activated protein kinase in proliferation. GF109203X, Ro 31-8220, calphostin C, and chelerythrine (selective protein kinase C inhibitors) had no effect on PDGF-BB- or thrombin-stimulated DNA synthesis, suggesting that, despite abolishment of mitogen-stimulated protein kinase C activity, cell proliferation stimulated by PDGF-BB and thrombin is protein kinase C-independent. These data demonstrate that the PtdIns 3-kinase/protein kinase B pathway represents a key signaling route in airway smooth muscle proliferation, with the mitogen-activated protein kinase kinase 1/mitogen-activated protein kinase cascade providing a complementary signal required for the full mitogenic response.
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PMID:Platelet-derived growth factor-BB and thrombin activate phosphoinositide 3-kinase and protein kinase B: role in mediating airway smooth muscle proliferation. 985 29

Thrombin activates mast cells to release inflammatory mediators through a mechanism involving protease-activated receptor-1 (PAR-1). We hypothesized that PAR-1 activation would induce mast cell adhesion to fibronectin (FN). Fluorescent adhesion assay was performed in 96-well plates coated with FN (20 microg/ml). Murine bone marrow cultured mast cells (BMCMC) were used after 3-5 wk of culture (>98% mast cells by flow cytometry for c-Kit expression). Thrombin induced beta-hexosaminidase, IL-6, and matrix metalloproteinase-9 release from BMCMC. Thrombin and the PAR-1-activating peptide AparafluoroFRCyclohexylACitY-NH(2) (cit) induced BMCMC adhesion to FN in a dose-dependent fashion, while the PAR-1-inactive peptide FSLLRY-NH(2) had no effect. Thrombin and cit induced also BMCMC adhesion to laminin. Thrombin-mediated adhesion to FN was inhibited by anti-alpha(5) integrin Ab (51.1 +/- 6.7%; n = 5). The combination of anti-alpha(5) and anti-alpha(4) Abs induced higher inhibition (65.7 +/- 7.1%; n = 5). Unlike what is known for FcepsilonRI-mediated adhesion, PAR-1-mediated adhesion to FN did not increase mediator release. We then explored the signaling pathways involved in PAR-1-mediated mast cell adhesion. Thrombin and cit induced p44/42 and p38 phosphorylation. Pertussis toxin inhibited PAR-1-mediated BMCMC adhesion by 57.3 +/- 7.3% (n = 4), indicating that G(i) proteins are involved. Wortmannin and calphostin almost completely inhibited PAR-1-mediated mast cell adhesion, indicating that PI-3 kinase and protein kinase C are involved. Adhesion was partially inhibited by the mitogen-activated protein kinase kinase 1/2 inhibitor U0126 (24.5 +/- 3.3%; n = 3) and the p38 inhibitor SB203580 (25.1 +/- 10.4%; n = 3). The two inhibitors had additive effects. Therefore, thrombin mediates mast cell adhesion through the activation of G(i) proteins, phosphoinositol 3-kinase, protein kinase C, and mitogen-activated protein kinase pathways.
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PMID:Thrombin induces mast cell adhesion to fibronectin: evidence for involvement of protease-activated receptor-1. 1237 Mar 92

Fat deposition influences both meat quality and animal productivity. However, it is not clear how fat development is regulated in growing and fattening beef cattle. This study characterized proteomic changes in subcutaneous adipose tissue from steers fed a high-grain diet in an effort to understand the molecular mechanisms of fat development during feedlot production. Eight British-Continental crossbred steers had two subcutaneous adipose tissue biopsies at 12 and 15 mo of age. Protein expression in fat samples was profiled using liquid chromatography-tandem mass spectrometry (LC-MS/MS). During the finishing period, steers increased subcutaneous adipose tissue mass with concomitant changes in the proteome profile, but the nature of these changes varied among steers. The expression of 123 out of 627 identified proteins differed (P <: 0.05) between 2 ages. Functional analyses on differentially expressed proteins revealed that 20.2% of them were associated with cellular growth and proliferation of adipose tissue. There were 17 out of 108 differentially expressed proteins associated with lipid metabolism, which were acyl-CoA synthetase medium-chain family member 1 (ACSM1), annexin A1 (ANXA1), apolipoprotein C-III (APOC3), apolipoprotein H (beta-2-glycoprotein I; APOH), EH-domain containing 1 (EHD1), coagulation factor II (thrombin; F2), gelsolin (GSN), lamin A/C (LMNA), mitogen-activated protein kinase kinase 1 (MAP2K1), myosin, heavy chain 9, non-muscle (MYH9), orosomucoid 1 (ORM1), protein disulfide isomerase family A, member 3 (PDIA3), retinol binding protein 4, plasma (RBP4), renin binding protein (RENBP), succinate dehydrogenase complex, subunit A, flavoprotein (Fp; SDHA), serpin peptidase inhibitor, clade C (antithrombin), member 1 (SERPINC1), and serpin peptidase inhibitor, clade G (C1 inhibitor), member 1 (SERPING1). Further analysis of the expression levels of proteins associated with lipid metabolism indicated a downregulation in the synthesis of fatty acids at the cellular level at 15 compared to 12 mo of age. These results suggest that even though adipose tissue expanded, fat anabolism was reduced in adipocytes during growth, revealing a coordinated balance between subcutaneous fat mass and the cellular abundance of lipogenic proteins to control the rate of fat deposition in growing beef cattle. The findings observed in this study expand our understanding on how proteome of bovine adipose tissue is regulated during growth, which might help the development in the future of new strategies to manipulate adiposity in beef cattle in a manner that improves meat quality and animal productivity.
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PMID:Effect of age on bovine subcutaneous fat proteome: molecular mechanisms of physiological variations during beef cattle growth. 2489 5