Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Previous studies have established that cardiomyocytes express protease-activated receptor (PAR)-1, a high-affinity receptor for thrombin, which is also activated by the tethered-ligand domain sequence (SFLLRN) and which promotes inositol trisphosphate accumulation, stimulates extracellular signal-regulated protein kinase, and modulates contractile function. A single previous report identified PAR-1 as a hypertrophic stimulus, but there have been no subsequent investigations of the mechanism. This study reveals the coexpression of PAR-1 and PAR-2 (a second PAR, which is activated by trypsin/tryptase but not thrombin) by Northern blot analysis and compares their signaling properties in neonatal rat ventricular cardiomyocytes. SFLLRN and SLIGRL (an agonist peptide for PAR-2) promote inositol trisphosphate accumulation, stimulate mitogen-activated protein kinases (extracellular signal-regulated protein kinase and p38-mitogen-activated protein kinase), elevate calcium concentration, and increase spontaneous automaticity. SFLLRN (but not SLIGRL) also activates c-Jun NH(2)-terminal kinase and AKT. In keeping with their linkage to pathways that have been associated with growth and/or survival, SFLLRN and SLIGRL both induce hypertrophy. However, PAR agonists promote cell elongation, a morphology that is distinct from the uniform increase in cell dimension induced by alpha(1)-adrenergic receptor activation. These studies provide novel evidence that cardiomyocytes coexpress 2 functional PARs, which link to a common set of signals that culminate in changes in contractile function and hypertrophic growth. PAR actions may assume clinical importance in the border zone surrounding an infarction, where local proteolysis of PARs by serine proteases generated during inflammatory or thrombogenic pathways would elevate calcium concentration (setting the stage for arrhythmias), promote hypertrophic growth, and/or influence cardiomyocyte survival.
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PMID:Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. 1082 35

Protein kinase B (PKB) is a serine/threonine kinase that is activated by growth hormones and implicated in prevention of apoptosis, glycogen metabolism, and glucose uptake. A key enzyme in PKB activation is phosphatidylinositide 3-kinase (PI-3K), which triggers the dual phosphorylation of PKB by phosphatidylinositol-dependent kinases (PDKs). Here we report that the major PKB subtype in platelets is PKBalpha, which is activated by phosphorylation of Thr(308) and Ser(473) and has a constitutively phosphorylated Thr(450) that does not contribute to PKB activation. alpha-Thrombin and thrombopoietin activate PKBalpha via PI-3K and trigger the concurrent phosphorylation of Thr(308) (via PDK1) and Ser(473) (via a not yet identified PDK2). In addition, alpha-thrombin activates a PI-3K-independent pathway involving phospholipase Cbeta and calcium-dependent protein kinase C subtypes (PKCalpha/beta). This route is specific for phosphorylation of Ser(473) and can be initiated by direct PKC activation with phorbol ester or purified active PKC catalytic fragment in platelet lysate. Different degrees of Ser(473) and Thr(308) phosphorylation correlate with different degrees of enzyme activity. These data reveal a PI-3K-independent PKB activation in which PKCalpha/beta regulates the phosphorylation of Ser(473) in PKBalpha. The independent control of the two phosphorylation sites may contribute to fine regulation of PKBalpha activity.
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PMID:Dual regulation of platelet protein kinase B. 1087 27

Cathepsin G is a neutrophil-derived serine protease that contributes to tissue damage at sites of inflammation. The actions of cathepsin G are reported to be mediated by protease-activated receptor (PAR)-4 (a thrombin receptor) in human platelets. This study provides the first evidence that cathepsin G promotes inositol 1,4,5-trisphosphate accumulation, activates ERK, p38 MAPK, and AKT, and decreases contractile function in cardiomyocytes. Because some cathepsin G responses mimic cardiomyocyte activation by thrombin, a role for PARs was considered. Cathepsin G markedly activates phospholipase C and p38 MAPK in cardiomyocytes from PAR-1-/- mice, but it fails to activate phospholipase C, ERK, p38 MAPK, or AKT in PAR-1- or PAR-4-expressing PAR-1-/- fibroblasts (which display robust responses to thrombin). These results argue that PAR-1 does not mediate the actions of cathepsin G in cardiomyocytes, and neither PAR-1 nor PAR-4 mediates the actions of cathepsin G in fibroblasts. Of note, prolonged incubation of cardiomyocytes with cathepsin G results in the activation of caspase-3, cleavage of FAK and AKT, sarcomeric disassembly, cell rounding, cell detachment from underlying matrix, and morphologic features of apoptosis. Inhibition of Src family kinases or caspases (with PP1 or benzyloxycarbonyl-VAD-fluoromethyl ketone, respectively) delays FAK and AKT cleavage and cardiomyocyte detachment from substrate. Collectively, these studies describe novel cardiac actions of cathepsin G that do not require PARs and are predicted to assume functional importance at sites of interstitial inflammation in the heart.
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PMID:Neutrophil cathepsin G promotes detachment-induced cardiomyocyte apoptosis via a protease-activated receptor-independent mechanism. 1270 81

All vascular cells, including endothelial cells and smooth muscle cells, express components of the leukocyte NADPH oxidase such as p22phox, p47phox, and Rac. Endothelial cells and fibroblasts also express the leukocyte NADPH oxidase subunit gp91phox/nox2, whereas in smooth muscle cells nox1 and nox4 are found. The different vascular NADPH oxidases represent important sources for the basal as well as the agonist-induced superoxide anion (O(2) .-) generation in the vasculature. In vascular smooth muscle cells, activation of the NADPH oxidases and the subsequent formation of O(2) .- has been demonstrated for various agents including angiotensin II, thrombin, lysophosphatidylcholine, and tumor necrosis factor alpha. By influencing the activity of p38 mitogen-activated protein kinase and AKT, NADPH oxidase-derived O(2) .- increases the expression of several pro-arteriosclerotic genes, such as monocyte chemoattractant protein-1, tissue factor, and vascular endothelial growth factor. Thus, the vascular NADPH oxidases play an important role in mediating the signal transduction cascade of pro-arteriosclerotic stimuli.
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PMID:Role of NADPH oxidases in the control of vascular gene expression. 1458 54

Thrombin cleavages of selective proteinase-activated receptors (PAR) as well as PAR-activating peptide ligands can initiate the phosphoinositide 3-kinase (PI3K) signaling cascade in platelets. Downstream to this event, fibrinogen receptors on platelets undergo conformational changes that enhance fibrinogen binding. In our study, we used this phenomenon as a surrogate biomarker for assessing effects on PI3K activity. Our method, using flow cytometric measurement of fluorescent ligand and antibody binding, uncovered a 16- to 45-fold signal window after PAR-induced platelet activation. Pretreatment (in vitro) with the PI3K inhibitors wortmannin and LY294002 resulted in concentration-dependent inhibition at predicted potencies. In addition, platelets taken from mice treated with wortmannin were blocked from PAR-induced ex vivo activation concomitantly with a decrease in phosphorylation of AKT from excised tumor xenografts. This surrogate biomarker assay was successfully tested (in vitro) on blood specimens received from volunteer cancer patients. Our results indicate that measurement of platelet activation could serve as an effective drug activity biomarker during clinical evaluation of putative PI3K inhibitors.
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PMID:A platelet biomarker for assessing phosphoinositide 3-kinase inhibition during cancer chemotherapy. 1776 38

TP508 is a synthetic 23-amino acid peptide representing a receptor-binding domain of human thrombin. We have previously shown that a single injection of TP508 accelerates fracture healing in a rat femoral fracture model. To understand how TP508 acts at the protein level during fracture healing, we compared the translational profiles between saline-control and fractured femur at six time points after TP508 treatment using the second generation of BD Clontechtrade mark Antibody Microarray. Here, we demonstrate that TP508 accelerates fracture healing by modulating expression levels of proteins primarily involved in the functional categories of cell cycle, cellular growth and proliferation, and cell death. The majority of those proteins are physically interrelated and functionally overlapped. The action of those proteins is highlighted by a central theme of promoting cell growth via balance of cell survival over cell death signals. This appears to occur through the stimulation of several bone healing pathways including cell cycle-G1/S checkpoint regulation, apoptosis, JAK/STAT, NF-kappaB, PDGF, PI3K/AKT, PTEN, and ERK/MAPK.
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PMID:TP508 accelerates fracture repair by promoting cell growth over cell death. 1794 78

Phosphoinositide (PI) 3-kinase (PI3K) signaling processes play an important role in regulating the adhesive function of integrin alpha(IIb)beta(3), necessary for platelet spreading and sustained platelet aggregation. PI3K inhibitors are effective at reducing platelet aggregation and thrombus formation in vivo and as a consequence are currently being evaluated as novel antithrombotic agents. PI3K regulation of integrin alpha(IIb)beta(3) activation (affinity modulation) primarily occurs downstream of G(i)-coupled and tyrosine kinase-linked receptors linked to the activation of Rap1b, AKT, and phospholipase C. In the present study, we demonstrate an important role for PI3Ks in regulating the avidity (strength of adhesion) of high affinity integrin alpha(IIb)beta(3) bonds, necessary for the cellular transmission of contractile forces. Using knock-out mouse models and isoform-selective PI3K inhibitors, we demonstrate that the Type Ia p110 beta isoform plays a major role in regulating thrombin-stimulated fibrin clot retraction in vitro. Reduced clot retraction induced by PI3K inhibitors was not associated with defects in integrin alpha(IIb)beta(3) activation, actin polymerization, or actomyosin contractility but was associated with a defect in integrin alpha(IIb)beta(3) association with the contractile cytoskeleton. Analysis of integrin alpha(IIb)beta(3) adhesion contacts using total internal reflection fluorescence microscopy revealed an important role for PI3Ks in regulating the stability of high affinity integrin alpha(IIb)beta(3) bonds. These studies demonstrate an important role for PI3K p110 beta in regulating the avidity of high affinity integrin alpha(IIb)beta(3) receptors, necessary for the cellular transmission of contractile forces. These findings may provide new insight into the potential antithrombotic properties of PI3K p110 beta inhibitors.
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PMID:Phosphoinositide 3-kinase p110 beta regulates integrin alpha IIb beta 3 avidity and the cellular transmission of contractile forces. 1994 Jan 48

We observed that human rhabdomyosarcoma (RMS) cells highly express a tissue factor that promotes thrombin formation, which indirectly and directly affects RMS progression. First, we found that thrombin activates platelets to generate microvesicles (PMV), which transfer to RMS cells' alpha2beta3 integrin and increase their adhesiveness to endothelial cells. Accordingly, RMS cells covered with PMVs showed higher metastatic potential after i.v. injection into immunodeficient mice. Furthermore, PMVs activate mitogen-activated protein kinase (MAPK)p42/44 and AKT to chemoattract RMS cells. We also found that RMS cells express functional protease-activated receptor-1 (PAR1) and PAR3 and respond to thrombin stimulation by MAPKp42/44 and MAPKp38 phosphorylation. To our surprise, thrombin did not affect RMS proliferation or survival; it inhibited the chemotactic and adhesive properties of RMS cells. However, when PAR1-specific agonist thrombin receptor-activating peptide 6 was used, which does not activate PAR3, selective PAR1 stimulation enhanced RMS proliferation. To learn more on the role of PAR1 and PAR3 antagonism in RMS proliferation and metastasis, we knocked down both receptors by using a short hairpin RNA strategy. We found that although thrombin does not affect growth of PAR1(-/-) cells, it stimulated the proliferation of PAR3(-/-) cells. More importantly, PAR3(-/-) cells, in contrast to PAR1(-/-) ones, formed larger tumors in immunodeficient mice. We conclude that thrombin is a novel underappreciated modulator of RMS metastasis and that we have identified a novel role for PAR3 in thrombin signaling.
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PMID:Thrombin regulates the metastatic potential of human rhabdomyosarcoma cells: distinct role of PAR1 and PAR3 signaling. 2044 98

Expression of PAR, the thrombin receptor, is elevated in smooth muscle cell-rich areas in atherosclerotic plaques, where the cells change to proinflammatory or synthetic phenotype. In this study we investigated whether thrombin promotes a proinflammatory phenotype in vascular smooth muscle cell (VSMC), characterized by increased cytokine and chemokine synthesis. Thrombin not only elevated transcripts for IL-6, CXCL8, and CCL11 genes but also enhanced release of IL-6 and CXCL8 protein from human aortic smooth muscle cell (HAoSMC). Thrombin activated Akt, PKC and MAPK in HAoSMC, and thrombin-mediated expression of IL-6 and CXCL8 was significantly inhibited by LY294002, AKT IV, RO318220, and GF109203X as well as by diphenyleneiodium at the messenger RNA and the protein levels. SB202129 and U0126 also significantly attenuated thrombin-mediated release of IL-6 and CXCL8 proteins from HAoSMC. These results indicate that thrombin promotes proinflammatory phenotype in human VSMC and that PI3K, Akt, PKC, NADPH oxidase, and MAPK are involved in that process. We propose that activation VSMC in response to thrombin after endothelial injury and/or thrombus formation will enhance inflammation in vasculature.
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PMID:Thrombin promotes proinflammatory phenotype in human vascular smooth muscle cell. 2045 99


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