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)

Systemic Lupus Erythematosus (SLE) is a multisystem disease characterized by an increase in the spontaneous secretion of immunoglobulin (Ig) molecules, many of which are autoreactive. We have previously shown (Biochem & Biophys. Res. Comm. (1989) 161: 1319-1326) that normal human peripheral blood mononuclear cells (PBMCs) can be stimulated to secrete large quantities of Ig upon incubation with the protein kinase-C activator 1 oleoyl-2-acetyglycerol (OAG). Specific blockage of protein kinase C with the isoquinoline sulfonyl piperazine compound (H-7) inhibited the OAG-induced Ig production. In experiments reported here, PBMC of 5 patients with active SLE produced high levels of IgG spontaneously in culture. PBMC of 6 inactive SLE patients and 7 normal control subjects produced comparable low levels of IgG spontaneously. Pokeweed mitogen (PWM) stimulation of PBMC in inactive SLE and control groups, but not active SLE patients produced markedly enhanced IgG production. The lack of response to PWM stimulation in active SLE patients is likely due to inherent maximal stimulation of active SLE B-cells. In addition, we examined the ability of H-7 to inhibit both mitogen-stimulated (normal and inactive SLE) and spontaneous (active SLE) Ig production. In other experiments, we also examined the ability of the isoquinoline sulfonamide (HA-1004), a potent inhibitor of cAMP-dependent protein kinase to regulate mitogen stimulated and spontaneous Ig production in the patient groups indicated above. H-7 significantly inhibited PWM stimulated Ig production in normal (P less than 0.0001) and inactive SLE patients, (P less than 0.040) suppressing PWM stimulated levels to spontaneous levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of protein-kinase C in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: effect on spontaneous immunoglobulin production. 175 25

Cdk-interacting protein 1 (Cip1) is a p53-regulated 21-kDa protein that inhibits several members of the cyclin-dependent kinase (CDK) family. It was initially observed in complexes containing CDK4, cyclin D, and proliferating cell nuclear antigen (PCNA). PCNA, in conjunction with activator 1, acts as a processivity factor for eukaryotic DNA polymerase (pol) delta, and these three proteins constitute the pol delta holoenzyme. In this report, we demonstrate that Cip1 can also directly inhibit DNA synthesis in vitro by binding to PCNA. Cip1 efficiently inhibits simian virus 40 replication dependent upon pol alpha, activator 1, PCNA, and pol delta, and this inhibition can be overcome by additional PCNA. Simian virus 40 DNA replication, catalyzed solely by high levels of pol alpha-primase complex, is unaffected by Cip1. Using the surface plasmon resonance technique, a direct physical interaction of PCNA and Cip1 was detected. We have observed that Cip1 efficiently inhibits synthesis of long (7.2 kb) but not short (10 nt) templates, suggesting that its association with PCNA is likely to impair the processive movement of pol delta during DNA chain elongation, as opposed to blocking assembly of the pol delta holoenzyme. The implications of the Cip1-PCNA interaction with respect to regulation of DNA synthesis, cell cycle checkpoint control, and DNA repair are discussed.
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PMID:Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme. 791 43

1. The effects of the vasoconstrictor angiotensin II (Ang II) on whole-cell ATP-sensitive K+ currents (IK,ATP) of smooth muscle cells isolated enzymatically from rat mesenteric arteries were investigated using the patch clamp technique. 2. Ang II, at a physiological concentration (100 nM), reduced IK,ATP activated by 0.1 mM internal ATP and 10 microM levcromakalim by 36.4 +/- 2.3%. 3. The protein kinase C (PKC) activator 1-oleoyl-2-acetyl-sn-glycerol (OAG, 1 microM) reduced IK,ATP by 44.1 +/- 2.7%. GDP beta S (1 mM), included in the pipette solution, abolished the inhibition by Ang II, while that by OAG was unaffected. 4. Pretreatment with the PKC inhibitors staurosporine (100 nM) or calphostin C (500 nM) prevented the Ang II-induced inhibition of IK,ATP. 5. Ang II inhibition was unaffected by cell dialysis with PKA inhibitor peptide (5 microM), and the PKA inhibitor Rp-cAMPS (100 microM) did not reduce IK,ATP. 6. Our results suggest that Ang II modulates KATP channels through activation of PKC but not through inhibition of PKA.
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PMID:Angiotensin II inhibition of ATP-sensitive K+ currents in rat arterial smooth muscle cells through protein kinase C. 937 6

We investigated the effects of the phorbol ester phorbol 12-myristate 13-acetate (PMA) on the rapid component of the delayed rectifier potassium current, IKr, in guinea pig cardiomyocytes and found that the IKr current amplitude was reduced by 20% with 10 nM PMA and 44% with 100 nM PMA. The ether-a-go-go-related gene (HERG) encodes IKr in human heart. We expressed HERG heterologously in Xenopus oocytes and investigated the effects of PMA on the delayed rectifier potassium current. Upon application of PMA in a concentration of 100 nM, we found a similar reduction of HERG outward current amplitude by 59%. This reduction was due to a shift in the HERG activation curve by 37 mV. The ED50 for the PMA-induced shift was 9.0 nM. The inactive 4alpha-phorbol 12-myristate 13-acetate (4alpha-PMA) had no effect. PMA is known to act by stimulating distinct protein kinase cascades. Additional application of the specific protein kinase C inhibitors chelerythrine (10 microM) or bisindolylmaleimide (1 microM) could not attenuate the PMA-induced shift. In contrast, the shift by PMA was reduced significantly when the specific protein kinase A (PKA) inhibitors H89 (50 microM) or KT5720 (2.5 microM) were applied. Forskolin (400 microM), an activator of the adenylate cyclase that results in PKA activation, shifted the HERG activation curve by 14 mV. Moreover the specific protein kinase C activator 1-stearoyl-2-arachidonylglycerol (10 microM) showed no effect. Our data suggest that mainly PKA is mediating the shift of the HERG activation kinetics.
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PMID:HERG potassium channel activation is shifted by phorbol esters via protein kinase A-dependent pathways. 973 94

TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS). IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enzyme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms2). This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism. Here we report the purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism. We find that the TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13-Uev1A. Moreover, the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination. We also provide evidence that TRAF6 is conjugated by the K63 polyubiquitin chains. These results indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.
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PMID:TAK1 is a ubiquitin-dependent kinase of MKK and IKK. 2941 May 30

Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular protons. They are expressed in central and sensory neurons where they are involved in neuromodulation and in pain perception. Recently, the PDZ domain-containing protein PICK1 (protein interacting with C-kinase) has been shown to interact with ASIC1a and ASIC2a, raising the possibility that protein kinase C (PKC) could regulate ASICs. We now show that the amplitude of the ASIC2a current, which was only modestly increased ( approximately +30%) by the PKC activator 1-oleyl-2-acetyl-sn-glycerol (OAG, 50 microm) in the absence of PICK1, was strongly potentiated ( approximately +300%) in the presence of PICK1. This PICK1-dependent regulatory effect was inhibited in the presence of a PKC inhibitory peptide and required the PDZ domain of PICK1 as well as the PDZ-binding domain of ASIC2a. We have also shown the direct PICK1-dependent phosphorylation of ASIC2a by [(32)P]phosphate labeling and immunoprecipitation and identified a major phosphorylation site, (39)TIR, on the N terminus part of ASIC2a. The OAG-induced increase in ASIC2a current amplitude did not involve any change in the unitary conductance of the ASIC2a channel, whether co-expressed with PICK1 or not. These data provide the first demonstration of a regulation of ASICs by protein kinase phosphorylation and its potentiation by the partner protein PICK1.
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PMID:Protein kinase C stimulates the acid-sensing ion channel ASIC2a via the PDZ domain-containing protein PICK1. 1239 60

Protein kinase CK2 from neuronal chromatin phosphorylates myosin-like proteins isolated from rat brain chromatin. The protein kinase CK2 activator 1-ethyl-4,5-di(N-methylcarbamoyl)imidazole in vitro stimulated phosphorylation of myosin-like proteins and increased myosin-type Ca(2+)-ATPase activity in neuronal chromatin. After systemic administration this agent normalized Ca(2+)-ATPase activity of brain chromatin in aged rats.
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PMID:Protein kinase CK2 and regulation of Ca2+-ATPase activity in brain neuron chromatin in rats during aging. 1244 66

Reabsorption of phosphate in the proximal tubule is mainly mediated by the type IIa Na(+)/P(i) cotransporter (NaPi-IIa) and tightly regulated by a variety of factors including dietary phosphate intake and parathyroid hormone (PTH). PTH signals through both apical and basolateral PTH receptors and induces the rapid internalization and subsequent degradation of NaPi-IIa. At least two signalling cascades can be activated by PTH: the PLC/PKC and the cAMP/PKA pathways. Recent evidence from OK cell culture suggested the involvement of MAPK kinases in the PTH action. Here we used freshly isolated coronal mouse kidney slices and incubated them in a physiological buffer in the absence and presence of PTH with inhibitors and activators of the various signalling cascades to further study the events leading to internalization of NaPi-IIa. No alterations in the pattern of immunostaining for alpha-tubulin, actin and several brush border membrane proteins demonstrated intactness of the slices over the experimental period. Application of PTH (100 nM) induced a strong decrease of NaPi-IIa brush border staining and internalization after 45 min of incubation. The localization of the Na(+)/sulphate cotransporter (NaSi), however, was not affected. The internalization of NaPi-IIa could be completely prevented by the PKC inhibitor chelerythrine (1 micro M) or the MAPK-kinase (ERK1/2) inhibitor PD098059 (20 micro M). Without PTH both inhibitors alone had no effect. PTH induced phosphorylation of the ERK1/2 MAPK-kinases which was prevented by PD 098059. Separate activation of the cAMP/PKA pathway by 8-Br-cAMP was completely prevented by PD098059 whereas activation of the PLC/PKC pathway by the PKC activator 1,2-dioctanoyl-sn-glycerol (DOG) and the PKG pathway by 8-Br-cGMP induced internalization of NaPi-IIa which could be only partly blocked by PD 098059. Inhibition by SB203580 or activation by anisomycin of the p38 kinase pathway had no influence on NaPi-IIa localization under control conditions or after PTH stimulation. Furthermore, the PTH-induced decrease in NaPi-IIa protein could be reduced by PD 098059. These results suggest that the ERK1/2 MAPK kinase pathway plays a central role in the signalling of PTH leading to specific internalization and subsequent degradation of the type II NaPi-IIa cotransporter in the proximal tubule.
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PMID:Involvement of the MAPK-kinase pathway in the PTH-mediated regulation of the proximal tubule type IIa Na+/Pi cotransporter in mouse kidney. 1269 Apr 63

Single IK(Ca) channels of human erythrocytes were studied with the patch-clamp technique to define their modulation by endogenous protein kinase C (PKC). The perfusion of the cytoplasmic side of freshly excised patches with the PKC activator, phorbol 12-myristate 13-acetate (PMA), inhibited channel activity. This effect was blocked by PKC(19-31), a peptide inhibitor specific for PKC. Similar results were obtained by perfusing the membrane patches with the structurally unrelated PKC activator 1-oleoyl-2-acetylglycerol (OAG). Blocking of this effect was induced by perfusion with PKC(19-31) or chelerythrine. Channel activity was not inhibited by the PMA analog 4alpha-phorbol 12,13-didecanoate (4alphaPDD), which has no effect on PKC. Activation of endogenous cAMP-dependent protein kinase (PKA), which is known to up-modulate IK(Ca) channels, restored channel activity previously inhibited by OAG. The application of OAG induced a reversible reduction of channel activity previously up-modulated by the activation of PKA, indicating that the effects of the two kinases are commutative, and antagonistic. Kinetic analysis showed that down-regulation by PKC mainly changes the opening frequency without significantly affecting mean channel open time and conductance. These results provide evidence that an endogenous PKC down-modulates the activity of native IK(Ca) channels of human erythrocytes. Our results show that PKA and PKC signal transduction pathways integrate their effects, determining the open probability of the IK(Ca) channels.
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PMID:Modulation of Ca2+-activated K+ channels of human erythrocytes by endogenous protein kinase C. 1272 36

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuroprotective peptide which exerts its effects mainly through the cAMP-protein kinase A (PKA) pathway. Here, we show that in cortical neurons, PACAP-induced PKA signaling exerts a major part of its neuroprotective effects indirectly, by triggering action potential (AP) firing. Treatment of cortical neurons with PACAP induces a rapid and sustained PKA-dependent increase in AP firing and associated intracellular Ca(2+) transients, which are essential for the anti-apoptotic actions of PACAP. Transient exposure to PACAP induces long-lasting neuroprotection in the face of apoptotic insults which is reliant on AP firing and the activation of cAMP response element (CRE) binding protein (CREB)-mediated gene expression. Although direct, activity-independent PKA signaling is sufficient to trigger phosphorylation on CREB's activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression. Full activation is dependent on CREB-regulated transcription co-activator 1 (CRTC1), whose PACAP-induced nuclear import is dependent on firing activity-dependent calcineurin signaling. Over-expression of CRTC1 is sufficient to rescue PACAP-induced CRE-mediated gene expression in the face of activity-blockade, while dominant negative CRTC1 interferes with PACAP-induced, CREB-mediated neuroprotection. Thus, the enhancement of AP firing may play a significant role in the neuroprotective actions of PACAP and other adenylate cyclase-coupled ligands.
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PMID:Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1. 2162 92


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