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

Corticotropin signal transduction pathway involves serine/threonine protein phosphorylation. Recent reports suggest that protein tyrosine dephosphorylation may also be an integral component of that pathway. The present study was performed to investigate the role played by protein tyrosine phosphatases (PTPs) on acute response to corticotropin and the hypothetical regulation of PTPs by this hormone. We have used two powerful cell permeant PTP inhibitors, phenylarsine oxide (PAO) and pervanadate (PV), in order to examine the relevance of PTP activity on hormone-stimulated and 8-bromo-adenosine 3',5'-phosphate (8Br-cAMP is a permeant analogue of adenosine 3',5'-phosphate)-stimulated steroidogenesis in adrenal zona fasciculata (ZF) cells. In both cases, PAO and PV inhibited the steroid production in a dose-dependent fashion, and had no effect on steroidogenesis supported by a permeant analogue of cholesterol. The effect of hormonal stimulation on PTP activity was analyzed in rat adrenal ZF. In vivo corticotropin treatment reduced phosphotyrosine content in endogenous proteins and produced a transient increase of PTP activity in the cytosolic fraction, reaching a maximum (twofold) after 15 min. Incubation of adrenal ZF with 8Br-cAMP also produced PTP activation, suggesting that it can be mediated by cAMP-dependent protein kinase (PKA)-dependent phosphorylation. Detection of PTP activity in an in-gel assay showed three corticotropin-stimulated soluble PTPs with molecular masses of 115, 80 and 50 kDa. In summary, we report for the first time a hormone-dependent PTP activation in a steroidogenic tissue and provide evidence that PTP activity plays an important role in corticotropin signal pathway, acting downstream of PKA activation and upstream of cholesterol transport across the mitochondrial membrane.
...
PMID:Corticotropin increases protein tyrosine phosphatase activity by a cAMP-dependent mechanism in rat adrenal gland. 1051 84

The haematopoietic protein tyrosine phosphatase (HePTP) is a negative regulator of the MAP kinases Erk1, Erk2 and p38. HePTP binds to these kinases through a kinase-interaction motif (KIM) in its non-catalytic amino terminus and inactivates them by dephosphorylating the critical phosphorylated tyrosine residue in their activation loop. Here we show that cyclic-AMP-dependent protein kinase (PKA) phosphorylates serine residue 23 in the KIM of HePTP in vitro and in intact cells. This modification reduces binding of MAP kinases to the KIM, an effect that is prevented by mutation of serine 23 to alanine. The PKA-mediated release of MAP kinase from HePTP is sufficient to activate the kinase and to induce transcription from the c-fos promoter. Expression of a HePTP serine-23-to-alanine mutant inhibits MAP-kinase dissociation and activation and induction of transcription from the c-fos promoter. We conclude that HePTP not only controls the activity of MAP kinases, but also mediates crosstalk between the cAMP system and the MAP-kinase cascade.
...
PMID:Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase. 1055 44

The suppressive effect of genistein on osteoclast-like multinucleated cells from rat femoral tissues was investigated. The bone cells isolated from rat femoral tissues were cultured for 48 h in an alpha-minimal essential medium (5% fetal bovine serum) containing either vehicle or genistein (10(-7)-10(-5) M). Osteoclasts were estimated by staining for tartrate-resistant acid phosphatase, a marker enzyme of osteoclasts. The presence of genistein caused a significant decrease in the number of osteoclasts. Such a decrease was also seen in the presence of calcium choride (10(-5) M). Magnesium chloride (10(-5)-10(-3) M), a blocker of Ca2+ channels, had no effect on the number of osteoclasts. The effect of genistein (10(-5) M) or calcium (10(-3) M) in decreasing osteoclasts was significantly prevented by the presence of magnesium (10-3 M). Vanadate (10(-6)-10(-4) M), an inhibitor of protein tyrosine phosphatase activity, did not have an effect on the number of osteoclasts. The genistein's effect was not altered by vanadate. When isolated osteoclasts were cultured for 24 h in the presence of genistein (10(-7)-10(-5) M), protein kinase activity in the 5500 g supernatant of homogenate of the cells was significantly decreased, while protein tyrosine phosphatase activity was significantly elevated. Such an effect was also seen by the addition of genistein (10(-7)-10(-5) in the enzyme reaction mixture in vitro. The present study suggests that the suppressive effect of genistein on rat bone osteoclasts is partly involved in the inhibition of protein kinase and the activation of protein tyrosine phosphatase in osteoclasts.
...
PMID:Suppressive effect of genistein on rat bone osteoclasts: involvement of protein kinase inhibition and protein tyrosine phosphatase activation. 1067 66

The effects of protein tyrosine kinase (PTK) and PTK inhibitors on the GABAA receptor function were studied in cultured frog pituitary melanotrophs by using the patch-clamp technique. Extracellular application of the PTK inhibitors genistein (10-9 to 10-5 M) or lavendustin A (10-12 to 10-7 M) provoked a bell-shaped potentiation of the whole-cell current induced by GABA (3x10-6 M). In contrast, at high concentrations, genistein (10-4 M) and lavendustin A (10-5 M) reversibly reduced the GABA-evoked current. Daidzein and lavendustin B, the inactive analogs of genistein and lavendustin A, respectively, did not modify the current induced by GABA. In the inside-out configuration, bath application of the recombinant PTK pp60c-src (75 U/ml) inhibited the GABA-activated chloride current, and the inhibitory effect of pp60c-src was prevented by genistein (10-7 M). Immunoblotting revealed that genistein, at doses of 10-7 M or 10-4 M, markedly inhibited tyrosine phosphorylation of the beta2/beta3 subunits of the GABAA receptor. Extracellular application of the PKA activator Bt2cAMP (10-3 M), the PKA/PKC inhibitor H7 (10-5 M) and the Cam KII inhibitor W7 (10-5 M) reversibly diminished the whole-cell GABA-induced current. Internal application of H7 and W7 (10-4 M) did not modify the dose-dependent effects of genistein. Internal application of sodium orthovanadate (10-4 M), a protein tyrosine phosphatase inhibitor, decreased the GABA-evoked current and markedly reduced the potentiating effect of genistein. The present study provides the first evidence that, in frog pituitary melanotrophs, the GABAA receptor is phosphorylated at least on its beta2/beta3 subunits by an endogenous PTK. Our data also demonstrate that tyrosine phosphorylation exerts an inhibitory effect on GABAA receptor function.
...
PMID:Regulation of GABAA receptor by protein tyrosine kinases in frog pituitary melanotrophs. 1069 42

Protein tyrosine phosphorylation and dephosphorylation are important in the regulation of cell proliferation and signaling cascade. In order to examine whether phosphatase activity of CPTP1 and HPTP1B, typical nontransmembrane protein tyrosine phosphatase, could be controlled by phosphorylation, affinity-purified PTPs were phosphorylated by CKII and p56lck in vitro. Phosphoamino acid analysis revealed that CPTP1 was phosphorylated on both serine and threonine residues by CKII, and tyrosine residue by p56lck. Phosphatase activity of CPTP1 was gradually increased by three-fold concomitant with phosporylation by CKII. Phosphorylation of HPTP1B by CKII resulted in quick two-fold enhancement of its phosphatase activity within 5 min of incubation and remained in that state. In the presence of CKII inhibitor, heparin or poly(Glu.Tyr), both phosphorylation and enhancement of phosphatase activity of CPTP1 and HPTP1B were mostly blocked. p56lck catalyzed tyrosine phosphorylation of CPTP1 and HPTP1B was only observed by inhibiting the intrinsic tyrosine phosphatase activity. Taken together, these results indicate that CPTP1 or HPTP1B possesses a capability to regulate its phosphatase activity through phosphorylation processes and may participate in the cellular signal cascades.
...
PMID:Regulation of chicken protein tyrosine phosphatase 1 and human protein tyrosine phosphatase 1B activity by casein kinase II- and p56lck-mediated phosphorylation. 1076 62

The striatal-enriched protein tyrosine phosphatase (STEP) family is expressed within dopaminoceptive neurons of the CNS and is particularly enriched within the basal ganglia and related structures. Alternative splicing produces several isoforms that are found in a number of subcellular compartments, including postsynaptic densities of medium spiny neurons. The variants include STEP(61), a membrane-associated protein, and STEP(46), a cytosolic protein. The C terminals of these two isoforms are identical, whereas the N-terminal domain of STEP(61) contains a novel 172 amino acid sequence that includes several structural motifs not present in STEP(46). Amino acid sequencing revealed a number of potential phosphorylation sites in both STEP isoforms. Therefore, we investigated the role of phosphorylation in regulating STEP activity. Both STEP(61) and STEP(46) are phosphorylated on seryl residues by a cAMP-dependent protein kinase (PKA)-mediated pathway in striatal homogenates. The specific residues phosphorylated in STEP(61) were identified by site-directed mutagenesis and tryptic phosphopeptide mapping as Ser160 and Ser221, whereas the major site of phosphorylation in STEP(46) was shown to be Ser49. Ser160 is located within the unique N terminal of STEP(61). Ser221 and Ser49 are equivalent residues present in STEP(61) and STEP(46), respectively, and are located at the center of the kinase-interacting motif that has been implicated in protein-protein interactions. Phosphorylation at this site decreases the activity of STEP in vitro by reducing its affinity for its substrate. In vivo studies using striatal slices demonstrated that the neurotransmitter dopamine leads to the phosphorylation of STEP via activation of D1 receptors and PKA.
...
PMID:The Dopamine/D1 receptor mediates the phosphorylation and inactivation of the protein tyrosine phosphatase STEP via a PKA-dependent pathway. 1090

The current understanding of kit signaling is that a limited number of signaling proteins interact to build multiple interacting networks that allow diverse cellular responses. Cytoplasmic signaling proteins are increasingly seen to form networks directed through converging and interacting pathways rather than following a simple linear model. There are also numerous cross-connections between signaling proteins more distal to the receptor. Ras thus binds PI3 kinase and potentiates its activation, whereas the Rac-dependent protein kinase PAK phosphorylates MEK and thereby stabilizes its association with Raf. A signaling network with multiple intersecting pathways can obtain a single, coherent response from numerous, potentially conflicting signals. There is still limited information about the effect of activating mutations on various aspects of kit signaling. There is, however, mounting evidence that an activating mutation may enhance kit signaling and also induce factor-independent activation of kit. For instance, this activation could occur through degradation of SHP-1, the protein tyrosine phosphatase that negatively regulates kit signaling. There is also emerging evidence that inherent inhibitory factors may exist in the juxtamembrane of kit and may be suppressed as a result of a mutation in that region. Understanding the impact of these activating mutations on kit signaling is important, not only in contributing to the understanding of the pathogenesis of mastocytosis but ultimately in forming the basis for more effective therapeutic intervention in this disease.
...
PMID:Kit signal transduction. 1090 38

The inhibitory GABA(A) receptor is a key element in determining the pattern of nerve cell electrical activity. Thus, modulation of its function is of paramount impact in shaping neuronal functional activity under physiological and pathological conditions. This applies to cerebellar granule neurons as to all the other neurons in the brain. The culture of cerebellar granules from newborn rats is a convenient means by which to approach these cells for electrophysiological studies provided that they maintain, as far as GABA(A) receptors are concerned, the same characteristics as in situ. Thus, the regulation of GABA(A) receptor activity in these neurons has been studied by the patch-clamp technique, both in the whole-cell and outside-out configuration. An obvious first level of control of such receptors' activity is their desensitization under continued agonist application, with biphasic kinetics. The data do not allow one to conclude whether one is dealing with two different populations of receptors or with a single population with two desensitization phases; although the presence of two GABA(A) receptor populations is suggested by a host of observations. The granule cell GABA(A) receptors are modulated by changes in extracellular pH with lower pH resulting in an enhanced receptor activity. They display, under the conditions of whole-cell recording, a run-down phenomenon which is most probably due to a tyrosine phosphatase activity which is in turn under control by a protein serine kinase. Thus, in situ tyrosine phosphorylation is a key element in determining the efficiency of GABA mediated inhibition. Activation of protein kinase A or protein kinase G (PKG) down-regulates GABA(A) receptors' activity. This last event is involved in the depression of those receptors' activity by L-arginine via the production of nitric oxide. In addition, the activity of calmodulin-activated adenylate cyclase I is controlled by GABA(B) receptors. Dendritic GABA(A) receptor activity is partially blocked by previous activation of N-methyl-D-aspartate (NMDA) receptors via calcineurin mediated dephosphorylation/activation of protein tyrosine phosphatase and concomitant production of nitric oxide and PKG activation. The site phosphorylated by PKG is evidently not available for calcineurin-mediated serine dephosphorylation, due to calcineurin-specific membrane localization in respect of the GABA(A) receptor. Overall, a complex network of biochemical signals appear to keep granule cells GABA(A) receptors under a fine balance between up- and down-regulatory mechanisms. The overall data appear also to indicate the presence of two GABA(A) receptor populations: a dendritic one which can be modulated by Ca++ entering via NMDA receptors and a cell body one. The two populations are probably different in terms of desensitization kinetics and benzodiazepine sensitivity.
...
PMID:GABA(A) receptor modulation in rat cerebellum granule cells. 1095 91

The translocation of regucalcin to the nuclei of normal rat liver was investigated. The existence of endogenous regucalcin in isolated liver nuclei was confirmed by Western blotting using anti-regucalcin antibody. Nuclear translocation of regucalcin was estimated by sodium sulfate-polyacrylamide gel electrophoresis analysis. When isolated liver nuclei were incubated in the presence of exogenous regucalcin (50 microg/ml; 1.5 microM), potent band for regucalcin was found in the nuclei, indicating that the protein is translocated into the nucleus. This translocation was an early event. Nuclear regucalcin translocation was not appreciably changed in the presence of adenosine 5'-triphosphate (2 mM), guanosine 5'-triphosphate (2 mM), calcium chloride (0.1 mM), and the lectin wheat germ agglutinin (50 or 100 microg/ml), suggesting that its translocation is not mediated through nuclear localization signal. Moreover, Ca2+-dependent protein kinase and protein tyrosine phosphatase activities in isolated liver nuclei were significantly increased in the presence of anti-regucalcin monoclonal antibody (100 ng/ml) in the enzyme reaction mixture, and these increases were completely abolished by the addition of regucalcin (50 microg/ml). This study demonstrates that regucalcin is translocated into liver nucleus, and that it can regulate the nuclear function.
...
PMID:Translocation of regucalcin to rat liver nucleus: involvement of nuclear protein kinase and protein phosphatase regulation. 1107 24

The mitogen activated protein (MAP) kinase cascade represents one of the major regulator of cell growth by hormones and growth factors. However, although the activation of this intracellular pathway has been often regarded as mediator of cell proliferation, in many cell types the increase in MAP kinase (also called extra-cellular signal regulated kinase: ERK) activity may result in cell growth arrest, depending on the length or the intensity of the stimulation. In this review we examine recent data concerning the effects of somatostatin on the MAP kinase cascade through one of its major receptor subtype, the somatostatin receptor 1 (SSTR1), stably expressed in CHO-K1 cells. Somatostatin inhibits the proliferative effects of basic FGF (bFGF) in CHO-SSTR1 cell line. However, in these cells, somatostatin robustly activates the MAP kinase and augments bFGF-induced stimulation of ERK. We show that the activation of ERK via SSTR1 is mediated by the betagamma subunit of a pertussis toxin-sensitive G-protein and requires both the small G protein Ras and the serine/threonine kinase Raf-1. Moreover the phosphatidyl inositol-3kinase and the cytosolic tyrosine kinase c-src participate in the signal transduction regulated by SSTRI to activate ERK, as well as it is involved the protein tyrosine phosphatase (PTP) SHP-2. Previous studies have suggested that somatostatin-stimulated PTP activity mediates the growth inhibitory actions of somatostatin, in CHO-SSTR1 cells. Thus, the activation of SHP-2 by SSTR1 may mediate the antiproliferative activity of somatostatin. SHP-2 may. in turn, regulate the activity of kinases upstream of ERK that require tyrosine dephosphorylation to be activated, such as c-src. Finally, the synergism between somatostatin and bFGF in the activation of ERK results in an increased expression of the cyclin-dependent kinase inhibitor p21cip/WAF1 as molecular effector of the antiproliferative activity of somatostatin.
...
PMID:Somatostatin receptor 1 (SSTR1)-mediated inhibition of cell proliferation correlates with the activation of the MAP kinase cascade: role of the phosphotyrosine phosphatase SHP-2. 1108 1


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

---