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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombopoietin (TPO), also known as the c-mpl ligand, stimulates rapid tyrosine phosphorylation of multiple proteins in human platelets including the Janus family kinases JAK2 and TYK2. On its own, TPO has no effect on platelet aggregation and dense-granule secretion but induces a general potentiation of these responses by other stimuli. The most dramatic effect is observed against threshold concentrations of agonists for aggregation. Shape change or weak reversible aggregation induced by low concentrations of thrombin, collagen and the thromboxane mimetic, U46619, are converted into irreversible aggregation in the presence of TPO. A similar result is obtained in the presence of the ADP scavenger apyrase and cyclo-oxygenase inhibitor indomethacin. TPO also induces potentiation of dense-granule secretion measured through release of 5-hydroxy[3H]-tryptamine. This effect is most striking against low concentrations of stimuli and is independent of aggregation as it is observed in the presence of chelation of extracellular Ca2+ with EGTA. TPO potentiates activation of phospholipase C and elevation of intracellular Ca2+, providing a molecular explanation for potentiation of functional responses. TPO may have an important physiological role in priming platelet activation in thrombocytopenia, an action that may help to compensate for the reduced platelet density.
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PMID:Thrombopoietin potentiates activation of human platelets in association with JAK2 and TYK2 phosphorylation. 864 38

In this review, the role of tyrosine kinases in angiotensin II-mediated signal transduction pathways in vascular smooth muscle is discussed. Angiotensin II was isolated by virtue of its vasoconstrictor abilities and has long been thought to play a critical role in hypertension. However, recent studies indicate important roles for angiotensin II in inflammation, atherosclerosis, and congestive heart failure. The expanding role of angiotensin II indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Exciting recent data show that angiotensin II directly stimulates tyrosine kinases, including pp60(c-src) kinase (c-Src), focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2). Angiotensin II may activate receptor tyrosine kinases, such as Axl and platelet-derived growth factor, by as-yet-undefined autocrine mechanisms. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of Shc, Raf, and phospholipase C-gamma after angiotensin II stimulation. These angiotensin II-regulated tyrosine kinases appear to be required for angiotensin II effects, such as vasoconstriction, proto-oncogene expression, and protein synthesis, on the basis of studies with tyrosine kinase inhibitors. Thus, understanding angiotensin II-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. 913 Apr 41

Originally known to be a vasoconstrictor and thought to play a critical role in hypertension, angiotensin II has recently emerged to be important in inflammation, atherosclerosis and congestive heart failure. The expanding role of angiotensin II implies that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Recent data show that angiotensin II stimulates not only cytoplasmic tyrosine kinases including c-Src, focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2), but also may transactivate receptor tyrosine kinases such as Axl and PDGF by as yet undefined autocrine/paracrine mechanisms. Finally, tyrosine kinases, which mediate tyrosine phosphorylation of key signal mediators such as Shc, Raf, and phospholipase C-gamma following angiotensin II stimulation, remain to be defined. These tyrosine kinases, activated by angiotensin II, appear to be required for angiotensin II effects such as vasoconstriction, proto-oncogene expression, protein synthesis, and cell proliferation. Thus, it is important to understand angiotensin II-mediated signaling events, especially those related to tyrosine kinase activity, to develop new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle cells: role of tyrosine kinases. 921 88

In this review, the signal events regulated by angiotensin II (AngII) in vascular smooth muscle are analyzed based on activation of specific tyrosine kinases. AngII has been shown to play a critical role in the pathogenesis of hypertension, inflammation, atherosclerosis, and congestive heart failure. The expanding role of AngII indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Although at least three AngII receptors have been characterized, it seems that the AngII type I receptor (AT1R) is physiologically most important since pharmacologic inhibitors of the AT1R block most AngII signal events and have beneficial effects on cardiovascular disease. The AT1R is a seven transmembrane-spanning G protein-coupled receptor that regulates intracellular signal events by activation of Gq and Gi. However, many recent data indicate that activation of tyrosine kinases by several different mechanisms contributes to AngII effects in target tissues. Tyrosine kinases activated by AngII include c-Src, focal adhesion kinase (FAK), Pyk2 (CADTK), Janus kinases (JAK2 and TYK2), and the receptor tyrosine kinases Ax1, epidermal growth factor, and platelet-derived growth factor. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of paxillin, Shc, Raf, and phospholipase C-gamma after AngII stimulation. These AngII-regulated tyrosine kinases seem to be required for AngII effects such as vasoconstriction, proto-oncogene expression, and protein synthesis based on studies with tyrosine kinase inhibitors. Thus, understanding AngII-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. 989 42

Angiotensin II (AngII) plays a critical role in control of cardiovascular and renal homeostasis. In addition to its physiological action as a vasoconstrictor, growing evidence supports the notion that AngII contributes to cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. The physiological and pathological actions of AngII in adults are mediated largely via the AngII type 1 receptor (AT1R), a heterotrimeric G-protein-coupled receptor (GPCR). Besides coupling with heterotrimeric G proteins to activate phospholipase C-beta (PLC-beta), AT1R also activates receptor tyrosine kinases (PDGF-R, EGF-R and IGF-R) and non-receptor tyrosine kinases (Src, Fyn, Yes, proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK) and JAK2). These tyrosine kinases play critical roles in AngII-stimulated cell signal events.
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PMID:Angiotensin II signaling pathways mediated by tyrosine kinases. 1267 64

The signaling pathway for IFN-gamma-mediated induction of ICAM-1 expression was further studied in human NCI-H292 epithelial cells. The Tyr701 phosphorylation of signal transducer and activator of transcription 1 (STAT1) induced by interferon-gamma (IFN-gamma) and 12-O-tetradecanoylphorbol 13-acetate (TPA) was inhibited by the protein kinase C (PKC) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the Src kinase inhibitor PP2. An association between c-Src and STAT1 was increased by IFN-gamma and TPA, indicating the direct phosphorylation of STAT1 by PKC-dependent c-Src activation. Tyrosine phosphorylation of Janus kinases (JAK) 1/2 was induced by IFN-gamma but not by TPA. In addition, ICAM-1 promoter activity induced by IFN-gamma, but not that induced by TPA, was inhibited by the dominant-negative JAK1 and JAK2 mutants. IFN-gamma-induced tyrosine phosphorylation of phospholipase C (PLC)-gamma was inhibited by AG 490 (a JAK inhibitor), and the association between JAK1/2 and PLC-gamma was increased after IFN-gamma treatment, indicating the activation of PLC-gamma via JAK1/2 phosphorylation. ICAM-1 promoter activities induced by the overexpression of wild-type JAK1- and PLC-gamma2 were blocked by the PLCgamma2 mutant or the dominant-negative PKCalpha (Lys-->Arg), c-Src (Lys-->Met), or STAT1 (Y701M) mutants, but not by dominant-negative STAT3 (DN) mutants. These results confirmed that IFN-gamma activated PLC-gamma via JAK1/2 phosphorylation to induce PKC, c-Src, STAT1 activation, and ICAM-1 expression. The association between JAK1/2 and STAT1 was increased by IFN-gamma but not by TPA. It was inhibited by AG 490 but not by U73122, indicating the possible involvement of the JAK1/2-STAT1 pathway. All the results show that IFN-gamma induces ICAM-1 expression by two different pathways in NCI-H292 epithelial cells. One is the JAK1/2-dependent PLC-gamma pathway inducing the activations of PKCalpha, c-Src, and STAT1, and the other is the direct activation of STAT1 by JAK1/2.
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PMID:Differential role of Janus family kinases (JAKs) in interferon-gamma-induced lung epithelial ICAM-1 expression: involving protein interactions between JAKs, phospholipase Cgamma, c-Src, and STAT1. 1497 37

Neurotrophins exert many of their biological effects via the Trk receptor tyrosine kinases and require the regulated activation of distinct transcriptional and post-translational cellular events. Here we provide evidence for a novel signaling cascade from activated Trks to the transcription factor STAT5. Utilizing the STAT5 responsive element derived from the p21(WAF1/Cip1) promoter to modulate luciferase expression, neurotrophin-dependent activation of Trk A, B, and C was found to induce STAT5-mediated transcriptional response. Structure-function analysis using Trk A mutants in heterologous cells further revealed that the kinase activity and an intact phospholipase C-gamma binding site are required for STAT5 activation. In most cytokine responsive cell systems, STAT5 function is modulated by JAK2-dependent tyrosine phosphorylation. However, reconstitution studies using a JAK2 deficient cell line indicate that neurotrophin-induced STAT5 activation does not require the cognate upstream kinase JAK2. In contrast, the Src kinase inhibitor PP1 significantly abolishes STAT5-dependent transcription in Trk A expressing 293T cells and in BDNF-treated primary cortical neurons. Together these results suggest that neurotrophins may regulate neuronal gene expression via STAT5 in a JAK2 independent manner.
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PMID:Activation of STAT5-dependent transcription by the neurotrophin receptor Trk. 1570 76

The growth and metabolic actions of growth hormone (GH) are believed to be mediated through the GH receptor (GHR) by JAK2 activation. The GHR exists as a constitutive homodimer, with signal transduction by ligand-induced realignment of receptor subunits. Based on the crystal structures, we identify a conformational change in the F'G' loop of the lower cytokine module, which results from binding of hGH but not G120R hGH antagonist. Mutations disabling this conformational change cause impairment of ERK but not JAK2 and STAT5 activation by the GHR in FDC-P1 cells. This results from the use of two associated tyrosine kinases by the GHR, with JAK2 activating STAT5, and Lyn activating ERK1/2. We provide evidence that Lyn signals through phospholipase C gamma, leading to activation of Ras. Accordingly, mice with mutations in the JAK2 association motif respond to GH with activation of hepatic Src and ERK1/2, but not JAK2/STAT5. We suggest that F'G' loop movement alters the signalling choice between JAK2 and a Src family kinase by regulating TMD realignment. Our findings could explain debilitated ERK but not STAT5 signalling in some GH-resistant dwarfs and suggest pathway-specific cytokine agonists.
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PMID:An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway. 1848 18

Differentiation of PC12 cells by nerve growth factor (NGF) requires the activation of various mitogen-activated protein kinases (MAPKs) including p38 MAPK. Accumulating evidence has suggested cross-talk regulation of NGF-induced responses by G protein-coupled receptors, thus we examined whether NGF utilizes G(i/o) proteins to regulate p38 MAPK in PC12 cells. Induction of p38 MAPK phosphorylation by NGF occurred in a time- and dose-dependent manner and was partially inhibited by pertussis toxin (PTX). NGF-dependent p38 MAPK phosphorylation became insensitive to PTX treatment upon transient expressions of Galpha(z) or the PTX-resistant mutants of Galpha(i2) and Galpha(oA). Moreover, Galpha(i2) was co-immunoprecipitated with the TrkA receptor from PC12 cell lysates. To discern the participation of various signaling intermediates, PC12 cells were treated with a panel of specific inhibitors prior to the NGF challenge. NGF-induced p38 MAPK phosphorylation was abolished by inhibitors of Src (PP1, PP2, and SU6656) and MEK1/2 (U0126). Inhibition of the p38 MAPK pathway also suppressed NGF-induced PC12 cell differentiation. In contrast, inhibitors of JAK2, phospholipase C, protein kinase C and Ca(2+)/calmodulin-dependent kinase II did not affect the ability of NGF to activate p38 MAPK. Collectively, these studies indicate that NGF-dependent p38 MAPK activity may be mediated via G(i2) protein, Src, and the MEK/ERK cascade.
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PMID:Nerve growth factor-induced stimulation of p38 mitogen-activated protein kinase in PC12 cells is partially mediated via G(i/o) proteins. 1850 36

We have previously demonstrated that olanzapine-induced desensitization of 5-HT2A receptor-stimulated phospholipase C (PLC) activity is associated with increases in RGS7 protein levels both in vivo and in cells in culture, and the increase in RGS7 is dependent on activation of the JAK-STAT pathway in cells in culture. In the present study, we found that desensitization of 5-HT2A receptor-stimulated PLC activity induced by olanzapine is dependent on activation of the JAK-STAT pathway. Similar to olanzapine, clozapine-induced desensitization of 5-HT2A receptor signalling is accompanied by increases in RGS7 and activation of JAK2. Treatment with the selective 5-HT2A receptor antagonist MDL 100907 also increased RGS7 protein levels and JAK2 activation. Using a JAK2 inhibitor AG490, we found that clozapine and MDL 100907-induced increases in RGS7 are dependent on activation of the JAK-STAT pathway. Olanzapine, clozapine, and MDL 100907 treatment increased mRNA levels of RGS7. Using a chromatin immunoprecipitation assay we found STAT3 binding to the putative RGS7 promoter region. Taken together, olanzapine-induced activation of the JAK-STAT pathway, and STAT3 binding to the RGS7 gene could underlie the increase in RGS7 mRNA which could subsequently increase protein expression. Furthermore, the increase in RGS7 protein could play a role in the desensitization of 5-HT2A receptor signalling by terminating the activated Galphaq/11 proteins more rapidly. Overall, our data suggest that the complete desensitization of 5-HT2A receptor-stimulated PLC activity by olanzapine, clozapine and MDL 100907 requires activation of the JAK-STAT pathway, which in turn increases RGS7 expression probably by direct transcriptional activity of STAT3.
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PMID:Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907. 1897 43


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